Overview Articles

Linking the Primary Cilium to Cell

Migration in Tissue Repair and Brain
Development
IBEN RNN VELAND, LOUISE LINDBK, AND SREN TVORUP CHRISTENSEN

Keywords: primary cilia, cellular signaling, cell polarity, cell migration, development, tissue repair

ell migration is defined by the orchestrated lost via turnover of adherens and tight junctions. In mesenmovements of cells in particular directions to specific
chymal cell types, such as fibroblasts, the cyclic processes in
locations at specific points in time and is fundamental for
cell migration include membrane protrusion and substrate
immune responses, tissue homeostasis, and many developadhesion in the direction of movementthat is, at the
mental and morphogenic processes, such as gastrulation,
leading edge of the cellin concert with cell contraction,
neurulation, and organogenesis. Consequently, the impairdetachment, and retraction of the rear end. These steps
ment or enhancement of cell migration leads to severe
are continuously repeated during the course of the migradevelopmental disorders and diseases, including intellectual
tory event and are preceded by the establishment of the
disability, vascular disease, and defective immune responses,
cells anteriorposterior polarity, which is a prerequisite for
as well as cancer mortality due to metastasis, in which
directionality in cell migration (Etienne-Manneville 2012,
malignant cells invade the surrounding tissue (Cordeiro
2013, Bisi et al. 2013, Cordeiro and Jacinto 2013). The term
and Jacinto 2013, Takahashi et al. 2013, Valente et al. 2014,
planar cell polarity (PCP) usually refers to the polarization
Wells et al. 2013). Cell migration is generated by cyclic proof cells within the plane of a tissue, preceding collective cell
cesses that rely on tight regulation and continuous plasticity
migration or convergence extension movements, but is also
of the cytoskeleton, as well as a repositioning of cellular
frequently used to describe the anteriorposterior polarity
organelles, including Golgi, the centrosome, and the nucleus
in individually migrating cells. The molecular mechanisms
in the polarized cell (Insall and Machesky 2009, Etienneunderlying polarity establishment in addition to the nature
Manneville 2013, Holcomb et al. 2013, Maninov et al.
of cell protrusions can differ vastly between cell types and
2014). The Golgi apparatus resides in close proximity to the
among their extracellular environments (Doyle et al. 2013).
centrosome. During quiescence (growth arrest), the mother
Polarization occurs in response to positional cues, such
centriole constitutes a basal body for the formation of a prias chemical attractants or the disruption of contact with
mary cilium, which protrudes from the cell surface into the
neighboring cells that guide and adjust the cytoskeletal
extracellular environment (figure 1).
reorganization and the associated transport of proteins and
To functionally adapt to the migratory state in many
mRNA to the leading edge throughout the migratory promorphogenic, homeostatic, and metastatic processes, apicocess (Etienne-Manneville 2012, 2013, Cordeiro and Jacinto
basally polarized tissue cells undergo epithelial or endothe2013). In vivo, cell migration occurs in two dimensions, such
lial-to-mesenchymal-transition (EMT), whereby polarity is
as on a basal lamina, or in three dimensionsfor example,
BioScience 64: 11151125. The Author(s) 2014. Published by Oxford University Press on behalf of the American Institute of Biological Sciences. This is
an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
doi:10.1093/biosci/biu179

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Primary cilia are unique sensory organelles that coordinate cellular signaling networks in vertebrates. Inevitably, defects in the formation or
function of primary cilia lead to imbalanced regulation of cellular processes that causes multisystemic disorders and diseases, commonly known
as ciliopathies. Mounting evidence has demonstrated that primary cilia coordinate multiple activities that are required for cell migration, which,
when they are aberrantly regulated, lead to defects in organogenesis and tissue repair, as well as metastasis of tumors. Here, we present an
overview on how primary cilia may contribute to the regulation of the cellular signaling pathways that control cyclic processes in directional
cell migration.

Overview Articles
Primary
cilium

Schematic cross sections of the primary

cilium and the basal body (BB)

Receptor
Axonemal
protein

Cilioplasm

Ciliary
membrane

Axoneme

Ciliary
necklace

Plasma
membrane

9 outer
doublets of
MTs

Periciliary
membrane

Ciliary
membrane

Ciliary
pocket

Transition
fibers

Primary cilium
Anterograde
transport

Retrograde
transport

Basal body (BB)

9 triplets
of MTs

Centrosome

Transition
fibers

Arrays of MT
Primary
cilium

Primary
cilium
Centrosome

Nucleus

Direction of
migration

Figure 1. Outline of the primary cilium and modes of cell migration. (a) Primary cilia are microtubule (MT)-based, solitary organelles
that emanate from the centrosomal mother centriole (basal body, BB) at the cell surface during growth arrest in most vertebrate
cell types. An invagination at the cell membrane forms the ciliary pocket, in which transition fibers aid the docking of the BB to the
periciliary membrane. The ciliary necklace is part of the ciliary pore complex, which functions as a diffusion barrier for the trafficking
of proteins into and out of the cilium. The Golgi apparatus lies in close proximity to the base of the primary cilium. (b) The axoneme
of the cilium comprises nine outer doublets of MTs that extend from the A and B subfibers of triplet MTs in the basal body. (c) The
periciliary membrane is a site for the exocytosis and clathrin-dependent endocytosis in the dynamic trafficking of membrane and
axonemal proteins into and out of the cilium across the ciliary pore complex. (d) Hypothesis on cellular morphologies and ciliary
orientation in various migration modes. The orientation of the primary cilium toward the leading edge in 2D lamellipodium-based
migration is illustrated with an immunofluorescence microscopy image of a fibroblast migrating into the wound of a scratch assay.
The primary cilium (the open arrow) and arrays of microtubules projecting from the centrosome are stained with anti-acetylated
-tubulin (in blue). Source: Adapted with permission from Christensen and colleagues (2013). The lower insert shows the fibroblast
primary cilium protruding from the ciliary pocket by scanning electron microscopy analysis. Micrograph: Johan Kolstrup, Peter Satir.
(e) Fibroblast (1) lamellipodium formation and reorientation of the ciliacentrosome axis. Initial posterior positioning of the nucleus
(2) is followed by reorganization of the actin cytoskeleton, and reorientation of the ciliacentrosome axis (2). Migration is initiated
as the cilium points forward (3), and actin forces the membrane in the direction of the signal (4). (f) Tangentially migrating neurons
extend a leading process in the direction of migration (1). Movement is a two-step process, consisting of pushing (2) and pulling (3)
forces. First, a swelling occurs containing the Golgicentrosome axis, including the primary cilium. This event is accompanied by
pushing forces of actin or myosin at the posterior end (2). Simultaneously, pulling forces mediated by anterior MTs result in nuclear
translocation (3). During nuclear translocation, the primary cilium may transiently be resorbed (Baudoin et al. 2012). Abbreviations:
CCV, clathrin-coated vesicle; CMACs: cell-matrix adhesion complexes; CS, centriolar satellites; EE: early endosome; GDV, G
olgiderived vesicle. Color image available online at http://bioscience.oxfordjournals.org.
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Leading
edge (LE)

Overview Articles

Regulating the plasticity of the cytoskeleton during

migration
In the polarized cell, projections rich in filamentous actin
(F-actin), such as filopodia and lamellipodia, promote plasma
membrane protrusion at the leading edge. The formation of
these structures requires the nucleation, polymerization, and
branching of F-actin, in addition to polarized trafficking of
protrusion-promoting components to their sites of action
(Bisi et al. 2013). For instance, the Rho GTPases RhoA,
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Rac1, and Cdc42, in addition to a number of their associated

guanine nucleotide exchange factors and activator proteins
are essential regulators of many aspects of cell motility and
are tightly coupled to MT and actin dynamics (EtienneManneville 2013). The F-actin-based membrane protrusions are attached to the substrate and anchor the cell to
the substratum or ECM through integrin-mediated nascent
adhesions and focal complexes, some of which mature into
more-persistent focal adhesions. Collectively, these integrinbased transient structures can be referred to as cell-matrix
adhesion complexes (CMACs), and the tension on the actin
cytoskeleton that results from the dynamic formation and
turnover of CMACs is the main contributor to the forces
driving cellular relocation (Lock et al. 2008, Wolfenson et
al. 2011, Jacquemet et al. 2013). Contraction of the cell body
is generated by myosin motors on F-actin bundles, and the
release of CMACs, in combination with the cross-linking
and depolymerization of F-actin, allows for the cell body
contraction to be transmitted into retraction of the rear-end
(Wolfenson et al. 2011, Cramer 2013).
In addition to this dynamic receptor-mediated anchorage
of the cytoskeleton to the ECM, cell migration greatly relies
on the modification of the ECM through cellular traction
forces and matrix degradation by the actions of membranebound and secreted proteases (Vargova etal. 2012, Doyle et
al. 2013). Furthermore, CMACs detect ECM composition
and rigidity and integrate this into the cells protrusion rate,
migratory speed, and motility mode, while concomitantly
transmitting contractile forces from the cells actin cytoskeleton to the ECM (Lock et al. 2008, Huttenlocher and
Horwitz 2011). As an example of the former, fibroblasts can
alternate between modes of lamellipodia- and lobopodiabased motility, depending on ECM rigidity and composition
(Petrie et al. 2012).
The plasticity of the cytoskeleton and the remodeling of
ECM in the vicinity of the cell also rely on local changes in
ion concentrations and pH, which are regulated by transport
proteins in the cell membrane (Stock et al. 2013). Among these
is the sodiumhydrogen ion exchanger isoform NHE1, which
is essential for leading edge protrusion and is implicated in
several aspects of cell motility, including the regulation of pH
and cell volume, in addition to the branching, stabilization,
and anchorage of the actin cytoskeleton to the cell membrane
(Boedtkjer et al. 2012). Taken together, the actions repeatedly
executed by a migrating cell consist of a finely orchestrated
plethora of events, all of which rely on the previous events
in order to proceed. Various signaling systems partake in the
control of these events, including the sensing of chemotactic
gradients and the contact between the cell and the ECM. The
primary cilium can contribute to this in a number of ways, as
will be reviewed in the following sections.
The primary cilium points in the direction
of migration
Scratch assays and similar two-dimensional (2D) in vitro
migration approaches have been highly instructive in
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through connective tissues or between cells during tissue

invasion. Different cell types display various morphological characteristics as they migrate (figure 1d). In contrast
to fibroblasts, which primarily extend their leading edge
as a lamellipodium or lobopodium (figure 1e; Doyle et al.
2013), the stereotypic migrating neuron can form extensive
branched and elongated leading edge protrusions (Holcomb
et al. 2013). Furthermore, neuronal movement first requires
the elongation and stabilization of the leading protrusion
and forward motion of the centrosome, Golgi, and endoplasmatic reticulum, followed by nucleokinesisthat is, translocation of the nucleus (figure 1f; Guo and Anton 2014).
The directionality, speed, and persistence of cell migration,
in addition to EMT, are crucially regulated by a contextdependent series of cellular signaling systems, including
transforming growth factor beta/bone morphogenic protein
(TGF/BMP), receptor tyrosine kinase (RTK), wingless/
int (Wnt), hedgehog (Hh), and G-protein coupled receptor
(GPCR) pathways. The spatiotemporal polarization and
activation of these signaling systems may have diverse but
intersecting effects on the regulation of the cytoskeleton and
the dynamics of focal adhesions during tissue homeostasis,
as well as in developmental processes.
Primary cilia are microtubule (MT)-based organelles that
form as a single copy on the surface of most quiescent cells in
the human body (figure 1a1c). These cilia function as cellular sites for mechano-, chemo-, and osmosensation, which
regulate cellular processes during embryonic development
and in tissue homeostasis (Satir et al. 2010). Accordingly,
defects in ciliary assembly, maintenance, or function are
associated with a variety of genetic diseases and disorders,
such as early embryonic death, congenital heart disease, craniofacial and skeletal patterning defects, polycystic kidney
disease, cognitive disorders, anosmia, obesity, and tumorigenesis (Hildebrandt et al. 2011, Koefoed et al. 2014, Valente
et al. 2014). Notably, many of the signaling systems that control cell migration are also coordinated by primary cilia, such
as Hh, Wnt, TGF, and RTK signaling (Goetz and Anderson
2010, Christensen et al. 2012, Clement et al. 2013a, Oh and
Katsanis 2013). In this regard, mounting evidence shows that
defects in the formation or sensory function of primary cilia
are associated with a series of migration-related disorders
and diseases. Here, we present an overview of the function
of primary cilia in cell migration, with examples of how cilia
coordinate cellular signaling pathways and interact with the
extracellular matrix (ECM) during migratory responses.

Overview Articles

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signals need to be interpreted and integrated by the cell to

yield a behavior, directionality, and speed that, together, constitute the migratory response.
Defects in the formation, organization, or function of
primary cilia impair the cyclic processes of cell migration
(Lu et al. 2008, Tobin et al. 2008, Wu et al. 2009, Schneider et
al. 2010, Higginbotham et al. 2012, Jones et al. 2012, Rozycki
et al. 2014) and are associated with migration-related disorders in mice, including aberrant neurodevelopment and
brain abnormalities (Tobin et al. 2008, Baudoin et al. 2012,
Higginbotham et al. 2012, 2013) and abnormal skin wound
closure (Schneider et al. 2010), as well as defects in developmental morphogenesis and the repair of damaged corneal
epithelium (Blitzer et al. 2011). In the latter situation, tissue
repair is maintained by 2D migration of epithelial cells, in
which newly formed primary cilia and their associated basal
bodies move and orient toward the wound (Blitzer et al.
2011).
The interplay between primary cilia and RTK
signaling during cell migration
The primary cilium has been linked to coordination of
RTK signaling (Christensen et al. 2012), which regulates
migratory responses during development, as well as wound
healing and tissue renewal in mammals. The RTKs include
platelet-derived growth factor receptor alpha (PDGFR),
which localizes to primary cilia in various cell types and
is activated by its specific ligand, PDGF-AA, in cultures of
fibroblasts (Schneider et al. 2005). In scratch assays with
growth-arrested and ciliated wild type mouse embryonic
fibroblasts (MEFs), PDGF-AA increases the migration speed
and the directional movement of the cells, whereas cells
with stunted cilia caused by a hypomorphic mutation in
Ift88 (Tg737orpk MEFs), a gene required for ciliary assembly
through intraflagellar transport (Pedersen et al. 2008), display decreased directionality and no PDGF-AA responsiveness (Schneider et al. 2010). Similarly, fibroblasts isolated
from MeckelGruber syndrome patients with mutations in
the TMEM67/Meckelin fail to form primary cilia and have
in vitro migration phenotypes similar to that of Tg737orpk
MEFs (Barker et al. 2013).
PDGFR is encoded by a growth-arrest-specific gene,
such that receptor levels are upregulated in cultures of
fibroblasts after serum depletion and the formation of the
primary cilium (Schneider et al. 2005). Notably, receptor
expression in growth-arrested Tg737orpk MEFs is kept at a
basal level comparable to that of cycling cells (Schneider
etal. 2005), which could indicate that the lack of PDGF-AA
responsiveness in cilia-defective cells is due to lower levels of
receptor expression. However, activation of the basal levels of
PDGFR was detected neither in cycling wild type cells nor
in quiescent mutant cells after stimulation with PDGF-AA.
Using micropipettes to generate a PDGF-AA gradient, ciliated wild type MEFs in 2D cultures responded immediately
to a PDGF-AA injection and migrated uniformly toward
the pipette, whereas Tg737orpk MEFs did not respond to
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understanding the role of primary cilia in basic cell migration and invasion parameters such as speed, persistence,
and polarity (Christensen et al. 2013, McGowan and McCoy
2013). In scratch assays, cells are grown to confluence, followed by the introduction of a fine abrasion with a pipette
tip such that cells are able to migrate into the wound space.
Alternatively, a controlled, cell-free area can be created by
culturing cells with an insert or a barrier prior to monitoring. In many cases, cell cultures are depleted for serum in
order to induce growth arrest, which leads to the formation
of primary cilia; yet, many cell types spontaneously form
cilia in the presence of the serum, albeit in a less synchronized manner (Wheatley et al. 1994). One of the initial
events in 2D directed cell migration is the rearward movement of the nucleus in coordination with the repositioning
of the centrosome between the nucleus and the leading edge
(figure 1d; Maninov et al. 2014). This process depends on
the MT cytoskeleton, in addition to F-actin or intermediate
filaments (Etienne-Manneville 2013).
In 1977, Albrecht-Buehler published a seminal work on
the orientation of primary cilia in 2D cultures of growtharrested 3t3 fibroblasts (Albrecht-Buehler 1977). In confluent cultures with no cell migration, the ciliary orientation
appeared random, whereas the cilia on cells that migrated
in subconfluent cultures oriented predominantly in parallel to the culture substrate and to the direction of migration. Albrecht-Buehler (1977) inferred that primary cilia
are either passively oriented during cellular displacement
or that the cilium acts as a sensor or mechanotransducer,
which actively determines the directionality in cell migration. More recent in vitro studies (Christensen et al. 2008, Lu
et al. 2008, Wu et al. 2009, Schneider et al. 2010, McGowan
and McCoy 2013) have confirmed this unique reorientation
of the primary cilium at the wound site of migrating cells
(figure 1d, 1e), in which the cilium may directly interact with
ECM and control the orientation of the centrosome in front
of the nucleus. In some cases, the centrosome may localize
behind the nucleus in three-dimensional (3D) migrating
cells (Maninov et al. 2014), but it remains to be investigated
whether these cells are ciliated during the migratory event.
It is now evident that the position and orientation of primary cilia in the extracellular environment crucially define
their function in a variety of different cell types and tissues.
Prominent examples include the unique placement of primary cilia on the apical surface of apicobasally polarized
epithelial cells, as well as the positioning, projection, orientation, and even bending of cilia in deep tissues (Farnum
and Wilsman 2011). In this manner, the primary cilium, in
conjunction with the centrosome, may well play a significant
role in the integration of spatiotemporal cues that guide the
cyclic processes of movement and the placement of cells
during development and in tissue homeostasis. As follows,
the cilium could function as a point of reference for the
navigation of cells in an environment of both opposing and
synergistic signals, including soluble morphogens and variations in ECM composition, topography, and rigidity. These

Overview Articles
Direction of migration
Soluble signaling
molecules and mechanical load

Primary
cilium

Leading edge
(LE)

Vesicular trafficking
to leading edge (LE)

Migratory response:
Reorganization of
the cytoskeleton
Cell polarity
Adhesion dynamics
Directionality
Speed

Motor protein

Figure 2. (a) Schematic overview of ciliary signaling systems. The yellow segment of the cilium illustrates the inversin
compartment. (b) Specified ciliary signaling pathways may promote (+) the vesicular trafficking and targeting of proteins
to the leading edge of the migrating cell to control cell polarity processes. Insert: Localization of the calciumhydrogen
ion exchanger 1 (NHE1, in green) to the leading edge lamellipodium in a migrating fibroblasts. Tracks of microtubules
(MT) were stained with anti--tubulin (in blue) and F-actin with phalloidin (in magenta). The arrows indicate the
direction of NHE1 translocation. Source: Adapted with permission from Clement and colleagues (2013b). Abbreviations:
ECM, extracellular matrix; GPCR, G-protein coupled receptor; Hh, Hedgehog; RTK, Receptor tyrosine kinase; TGF,
transforming growth factor beta; Wnt, wingless/int. Color image available online at http://bioscience.oxfordjournals.org.
PDGF-AA and moved around randomly (Schneider et al.
2010). Similarly, time-lapse microscopy has demonstrated
that PDGF-AA increased the migration of postnatal lung
fibroblasts with primary cilia orienting toward the leading
edge (McGowan and McCoy 2013). Together, these findings
indicate that primary cilia are involved in the coordination
of PDGF-AA-mediated chemotaxis in fibroblasts.
The mechanisms by which cilia-mediated signaling is
converted into a migratory response are currently not well
understood. Questions evidently arise as to how signaling
within the cilium, which represents a very small and confined
compartment relative to the rest of the cell, and is able to
organize the initial steps in cellular adaptation to a gradient
of a chemoattractant and how this impinges on the cyclic
processes of guided movement. As will be outlined below,
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there are a number of observations that indicate the functional relationship between primary cilia and the regulation
of polarity signaling during the reorganization of the cytoskeleton in cell migration. Furthermore, recent observations
have shown that PDGF-AA-mediated migration in scratch
assays affects the targeted trafficking and activation of NHE1
to the leading edge of cells facing the wound (Schneider et
al. 2009, Clement et al. 2013b), at which the transporter reorganizes the actin cytoskeleton for the formation of a lamellopodium. This implies that ciliary signaling impinges on the
coordinated trafficking of specified polarity proteins along
microtubules to the leading edge (figure 2) or influences
the very positioning of microtubules tracks. Consequently,
the PDGF-AA-mediated speed and directionality of cell
migration is reduced in NHE1-null fibroblasts or in wild
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LE

Overview Articles

Wnt signaling and polarity processes in cell

migration
The Wnt signaling systems, which, in mammals, are initiated by the binding of 1 of 19 Wnt ligands to the family
of frizzled receptors (e.g., Fzd3) or context-dependent
coreceptors, regulate a series of diverse signal transduction
pathways to control embryonic processes during organogenesis and postnatal tissue homeostasis. Canonical Wnt
(Wnt/-cat) signaling operates via -catenin-mediated gene
transcription in cell proliferation and differentiation processes. Noncanonical Wnt responses are -catenin independent and regulate cell adhesion, motility, and polarization
during cell migration, such as in wound repair and during
the establishment of PCP. This is predominantly coordinated by disheveled (Dvl) proteins that elicit MT and
actin cytoskeletal remodeling via calcium-ion signaling or
through a number of Dvl interaction partners and downstream mediators (Gao and Chen 2010, Amin and Vincan
2012, Wynshaw-Boris 2012).
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The role of primary cilia in coordinating Wnt signaling

is unclear and subjected to much debate due to conflicting results on the requirement of the cilium in organizing
individual steps in Wnt signaling during embryonic or fetal
development (Ocbina et al. 2009, Wallingford and Mitchell
2011, Oh and Katsanis 2013). However, various Wnt signaling defects are associated with mutations affecting ciliary
composition, including the integrity of the basal body and
ciliary barriers, and a series of regulatory units in the Wnt
pathways localize to the cilia or centrosome axis, including Dvl proteins and -catenin, as well as components of
the -catenin destruction complex (Oh and Katsanis 2013,
Veland et al. 2013, Zilber et al. 2013). Furthermore, Fzd3,
which is a receptor for Wnt5a that promotes Wnt/PCP signaling and cell migration, has been localized to the primary
cilia of fibroblasts and kidney epithelial cells (Luyten et al.
2010, Veland et al. 2013), although the direct functionality of
this in terms of the ciliary control of cell migration remains
to be elucidated.
In support of a function of ciliary Wnt/PCP signaling in
directional cell migration, inversin/Nephrocystin-2 localizes
to a specific subset of the primary cilium, defined as the inv
compartment, which runs for about 2 micrometers above the
ciliary necklace region (figure 2a; Shiba et al. 2009). Inversin
acts at the decisive branch point between canonical and
noncanonical Wnt signaling by targeting cytoplasmic Dvl
for degradation, thus promoting -catenin turnover and
PCP (Simons et al. 2005). MEFs derived from the invs mouse
(invs/ MEFs) display decreased polarization and cell migration in 2D assays, associated with a dispersed accumulation
of GSK3-phosphorylated -catenin at the ciliary base,
elevated canonical Wnt signaling, and aberrant activation
and leading edge localization of RhoGTPases (Veland et al.
2013). Although these data indicate ciliary control of Wnt/
PCP signaling in the cyclic processes of guided movement,
inversin and other ciliary components affecting Wnt signaling also localize to extraciliary domains, such as the leading
edge of migrating cells, in which they may contribute to the
regulation of cell polarization and migration independently
of the cilium (Boehlke et al. 2013, Cui et al. 2013, Werner
et al. 2013). Most likely, Wnt signaling coordinates key spatiotemporal events during the cyclic processes of migration
through both cilia-dependent and independent pathways.
A number of observations link inversin to PDGFR
signaling in cell migration. Inversin is required for growtharrest-specific upregulation, as well as leading edge targeting
of NHE1, which are both defective in invs/ MEFs. This is
associated with dysregulated expression, leading edge targeting, and activation of ezrin/radixin/moesin proteins (Veland
et al. 2013), which crucially link NHE1 to the actin cytoskeleton and which are required for its activation (Denker
and Barber 2002). Moreover, invs/ MEFs fail to upregulate
PDGFR transcription during growth arrest, which leads to
decreased accumulation of PDGFR in the primary cilium,
and, consequently, responsiveness to PDGF-AA and activation of Akt and Mek1/2-Erk1/2 are reduced in these cells
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type cells in the presence of inhibitors of NHE1 activity

(Schneider et al. 2009). In this scenario, it was suggested that
PDGFR signaling activates the Akt and Erk1/2-Mek1/2-Rsk
pathways at the primary cilium. Downstream from here, the
Akt pathway may control focal adhesion formation and the
initiation of NHE1 translocation to the leading edge, where
the transporter is activated. Meanwhile, the Erk1/2-Mek1/2Rsk pathway may control the spatial organization of NHE1
translocation and incorporation that consequently specifies
the direction of the leading edge formation (Clement et al.
2013b). In line with this, the PI3K-Akt and Mek1/2-Erk1/2
pathways have been shown to play crucial roles in the initial
events of cell polarization in the 2D migration of growtharrested normal rat kidney epithelial cells (Bisel et al. 2008,
2013). Although ciliary formation, orientation, and function
were not assessed in these studies, the authors showed that
Mek1/2-Erk1/2 signaling is required for polarization of Golgi
and orientation of the centrosome in front of the nucleus,
whereas PI3K-Akt signaling is required for leading edge
targeting of the ganglioside GM1 prior to Golgi polarization
(Bisel et al. 2008, Bisel et al. 2013).
Additional classes of RTKs have been linked to primary
cilia. These include epidermal growth factor receptors and
insulin-like growth factor receptor 1 (Christensen et al.
2012, Higginbotham et al. 2013), the former of which localize to the primary cilium of human airway smooth muscle
cells (SMCs) and various neuronal subtypes and was suggested to play a part in mechanosensation and the directed
cell migration of SMCs (Wu et al. 2009). Evidently, further
studies will be needed to clarify how signaling through
PDGFR and other RTKs coordinate ciliary orientation and
the cyclic processes of migration and how this is carried out
in conjunction with other signaling systems, such as Hh signaling, which specifically affects the persistence but not the
speed of cell migration in ciliated postnatal lung fibroblasts
(McGowan and McCoy 2013).

Overview Articles
(Veland et al. 2007). On the basis of the accumulating data
on these signaling pathways, primary cilia, and cell migration, one may envisage the primary cilium as a site for crosstalking between different signaling pathways that regulate
the expression, targeting, and activation of key components
in polarity processes and directional cell migration. In this
regard, it will be interesting to investigate how functional
defects in inversin, Wnt, and PDGFR signaling are interrelated in ciliopathies.

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Primary cilia in tangentially migrating neurons

Interneurons migrate tangentially from regions of the
subpallium (the ganglionic eminences and the anterior
entopeduncular area) through the telencephalon in multiple
streams to populate areas of the neocortex, striatum, hippocampus, and olfactory bulb (Ayala et al. 2007, Guo and
Anton 2014). In the postnatal and adult brain, cell migration
remains. For instance, the positioning of granule neurons
in the cerebellum has defining consequences for the development of postural balance and symmetry in movements,
which are developed within the first years of life in humans
(Ghashghaei et al. 2007), and neuroblasts born in the lateral
ganglionic eminence continue to migrate along the rostral
migratory stream to the olfactory bulb throughout adulthood (Sawamoto et al. 2006).
The formation of polarized radial glia is the first step in
the construction of the cerebral cortex and will serve as a
scaffold for the oriented movement of newborn neurons,
which climb along glial projections to their target locations,
a migratory process that will proceed from gestational
week 12 throughout fetal development (Tau and Peterson
2010). Aberrant ciliary signaling resulting from the deletion of the small GTPase Arl13b, which is important for
ciliogenesis and the ciliary composition of signaling entities (Caspary et al. 2007), disrupts the formation of a polarized glial scaffold, which leads to neuronal misplacement
(Higginbotham et al. 2013). Although primary cilia have
not yet been implicated in the migratory process of radially migrating neurons, cilia are indirectly responsible for
proper neuronal migration in this scenario and may, in this
way, contribute to aberrant neurodevelopment and brain
abnormalities.
In a more direct manner, primary cilia were shown to affect
the tangential migration of interneurons. Gonadotrophinreleasing hormone (GnRH) neurons in mice migrate a long
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Primary cilia in neuronal migration and brain

development
Neuronal migration during embryonic and fetal development is essential for proper cytoarchitecture and function
of the brain (Guo and Anton 2014). Defective migration
consequently leads to a series of learning disabilities and
cognitive disorders, such as mental retardation and schizophrenia, which have been associated with defects in neuronal primary cilia (Hildebrandt et al. 2011, Valente et al. 2014).
Indeed, recent studies have shown a crucial link between
neuronal migration and the sensory capacity of primary cilia
in the developing brain that may rely on the spatiotemporal
dynamics of ciliary receptor composition (Higginbotham et
al. 2012, Higginbotham et al. 2013).
Development of the human brain is initiated at gestational week 3, at which the nervous system arises from a
uniform sheet of neuroectoderm, forming the neural plate.
The neural tube is formed as the ectodermal sheet closes
and the brain arises on excessive expansion of the most
cranial part of this structure (Tau and Peterson 2010).
Gradually, epithelial cells of the neural crest at the dorsalmost side of the neural tube will undergo EMT, deadhere,
and migrate as neural progenitors to their site of action. As
an example, projection neurons from the dorsal ventricular
zone migrate radially, whereas interneurons from regions in
the subpallium migrate tangentially into the olfactory bulb
or the cortex (Ayala et al. 2007). In radial migration, cells
originate in the dorsal part of the ventricular zone and crawl
along the extended processes of radial glial cells in order
to migrate to various destinations in the cortex. Tangential
migration is a mode of nonradial neuronal translocation,
predominantly exhibited by interneurons. Primary cilia
play a defining role in these events, including the formation
of the neural tube and Hh-regulated brain morphogenesis
(Tucker and Caspary 2013). The recent focus on ciliopathic
syndromes, of which several are associated with cognitive
impairment, including nephronophtisis, Joubert syndrome,
MeckelGruber syndrome, orofacial digital syndrome 1, and
BardetBiedl syndrome (Valente et al. 2014) have revealed a
link between primary cilia and cell migration in the developing brain. As an example, Joubert syndrome, a genetically
heterogenous ciliopathy in which all identified genetic mutations are linked to the primary cilium, is characterized by
heterotopia in several brain regions and compromised brain
tissue architecture (Juric-Sekhar et al. 2012). In addition,
although epithelial primary cilia usually project from the

apical membrane, some neural crest cells form primary cilia

at the basolateral side of the cell layer. This occurs as part of
the delamination of these ventricular neuroepithelial cells
as they undergo EMT. Because the basolaterally protruding primary cilia are formed adjacent to adherens junctions
and project into the ECM (Wilsch-Brauninger et al. 2012),
the question arises as to whether the cilium has a unique
function in directing cellular orientation in 3D migration
through ECM receptors in the primary cilium. The interactions of primary cilia and ECM will be discussed further
below, but these findings indicate that the primary cilium
and its positioning are tightly linked to the guidance of neuronal cell movements, although the necessity for a primary
cilium in controlling neuronal migration varies throughout
brain development and between cellular subtypes. In this
regard, it is noteworthy that neural crest cells with impaired
cilia formation due to the deletion of the integral basal body
component, BBS8, display marked migratory deficiency,
which has been linked to inferior Hh signaling in these cells
(Tobin et al. 2008).

Overview Articles

1122 BioScience December 2014 / Vol. 64 No. 12

primary cilia coordinate the signaling events required for

proper corticogenesis.
In summary, these discoveries emphasize the importance
of the primary cilium in coordinating neuronal migration
during brain development and reflect the necessity of the
spatiotemporal dynamics of ciliary receptor composition.
The primary cilium presents the cell with the ability to drastically increase local concentrations of receptors, allowing it
to respond to subtle environmental changes in the developing brain, and obscuring the system will inevitably have
devastating effects on the migration of developing neurons.
Further investigations should be directed at elucidating the
specific role for primary cilia in neuronal migration during
development, as well as in the postnatal brain, which allows
us to truly understand the complex circuitry of the mammalian brain and how disorganization may contribute to
developmental disorders. This could eventually lead to the
therapeutic guidance of newborn cells to damaged sites in
the brain.
Potential roles for interactions between primary cilia
and ECM in cell migration
Developmental and regenerative processes highly rely on
the cellular deposition of matrix components, as well as the
reorganization of existing ECM in connective tissues through
local tension forces combined with proteolytic activities.
During these events, the dynamic interplay between the cell
and ECM via CMACs is crucial in determining the cells
directionality, protrusion rate, and migratory speed. This
interplay is largely achieved by integrin signaling in combination with other pathways, including growth factor signalingfor instance, mediated by PDGF and epidermal growth
factor receptorsto control cytoskeletal plasticity (Lock et
al. 2008, Huttenlocher and Horwitz 2011, Vargova et al. 2012,
Jacquemet et al. 2013). Integrin heterodimers, the major
CMAC constituents, play a defining role in these processes
by forming a link between the actin cytoskeleton and ECM
components, such as fibronectin, collagen, and laminin, in
addition to various cell surface receptors, depending on the
combination of subunits (Huttenlocher and Horwitz 2011).
The primary cilium of numerous matrix-embedded cell
types, including fibroblasts, chondrocytes, and SMCs, project
from the cell surface into the ECM, while, to various extents,
emerging from a ciliary pocket (Farnum and Wilsman 2011).
Interestingly, these cilia have been found to harbor different
types of ECM receptors (McGlashan et al. 2006, Christensen
et al. 2008, Lu et al. 2008, Wu et al. 2009). The proteoglycan
NG2 and 2, 3, and 1 integrins localize to chondrocyte
primary cilia (McGlashan et al. 2006), and collagens, which
serve as ligands for the 31 integrins may associate with
the ciliary membrane at punctae appearing to correspond to
linkage sites between the axoneme and the ciliary membrane
(Jensen et al. 2004, McGlashan et al. 2006). ECM receptors
have also been documented in the membrane of primary
cilia of airway SMCs, which show elaborate accumulation of 2, 5, and 1 integrins (Wu et al. 2009), whereas
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distance from the nasal pit to the hypothalamic areas of the

forebrain during development (Shin et al. 2014), and disruption of ciliary formation by knockout of Kif3a, the gene
encoding a kinesin subunit required for intraflagellar transport (IFT) and ciliary assembly (Pedersen et al. 2008), leads
to an altered topographical distribution of GnRH neurons
(Shin et al. 2014). Although there was no apparent change
in the total number of migratory neurons across the path,
Kif3a/ mice displayed an increased number of neurons
in the rostral preoptic area of the rostral forebrain (Shin et
al. 2014). Kif3a has also been shown to control cortical MT
dynamics in MDCK cells (Boehlke et al. 2013), still, these
findings indicate a role for the primary cilium in specifying
the final location of a subpopulation of GnRH-producing
neurons during mouse development.
Indeed, in tangentially migrating neurons, the first
migration step is associated with ciliary exposure to the
membrane of the leading process. This is followed by a
directional change in which the cells switch from tangential
migration to radial migration. Guided by ciliary Hh signaling, cells exit their tangential path and continue into the
cortical plate (Baudoin et al. 2012). Disruption of ciliary
IFT genes and the inhibition of Hh signaling cause medial
ganglionic eminence (MGE) cells to retain their tangential
paths, which eventually leads to the loss of cortical gamma
aminobutyric acidproducing inhibitory interneurons
(Baudoin et al. 2012, Higginbotham et al. 2012). These findings indicate that the integrity of primary cilia in the developing cortex is required for Hh-mediated MT-cytoskeletal
organization, including the coordination of leading protrusion morphology and the guidance of neurons migrating
from the MGE to the cortical plate (Baudoin et al. 2012).
As opposed to randomly migrating Tg737orpk MEFs in 2D
cultures (Schneider et al. 2010), disorganized motility of
Arl13b-deficient neurons is accompanied by a retarded cell
displacement, mainly because of increased pausing between
migratory events (Higginbotham et al. 2012). Similarly,
both Kif3a- and Ift88/Polaris-deficient MGE cells with
defective primary cilia display decreased overall migration speed because of augmented pausing between these
events (Baudoin et al. 2012). This correlates with decreased
dynamics of ciliary length and movement relative to wild
type cells, in which the primary cilia display a range of
dynamic morphologies, especially during nonmigrating
periods, and appear to be probing the ECM for directional
cues (Higginbotham et al. 2012). Using microfluidic chambers for chemotaxis analysis, Arl13b-deficient interneurons
were shown to be unable to sense and respond properly to
extrinsic guidance cues secreted by dorsal cortical cells, most
likely because of alterations in ciliary receptor composition
of a series of neuronal GPCRs and RTKs (Higginbotham et
al. 2012). Therefore, Arl13b mutant interneurons displayed
aberrant activation of receptor-mediated effector molecules
in interneuron migration, including increased levels of
cyclic adenosine monophosphate and decreased activation
of Erk1/2, which supports the conclusion that interneuron

Overview Articles
signaling, which is partly coordinated through clathrindependent endocytosis at the base of primary cilia (Clement
et al. 2013a) can induce both EMT during heart development (Ezratty et al. 2011) and cilium-dependent differentiation of myofibroblasts from mesenchymal and epithelial
precursors. As part of the latter, in scratch assays, primary
cilia are resorbed in wound-proximal cells, rendering them
insensitive to PDGF-AA and Sonic Hh ligands during
their migratory response in vitro (Rozycki et al. 2014). The
exact mechanisms by which the primary cilium controls
persistent directionality in cell migration are currently
unknown but have been hypothesized to involve trafficking along stable MTs extending from the centrosome, in
which the ciliary basal body is anchored (Clement et al.
2013b). Future research should be directed at understanding
how the primary cilium in vivo acts as a signaling hub that
coordinates the cross-talking between signaling pathways
that are activated by chemotactic stimuli on one hand and
those triggered by ECM interactions on the other to control
migration-dependent processes throughout developmental
and in regenerative processes. Furthermore, it will be important to understand how these signaling pathways may either
depend on or exploit the primary cilium to control the cyclic
processes of cell movement.

Conclusions
The primary cilium may function as a point of reference
by organizing the spatiotemporal positioning of a cell in
three dimensions during tissue and organ development,
as well as in regenerative processes. A migratory response
crucially relies on the coordination of many different signaling systems, and specific receptors may become localized
to the primary cilium to coordinate the cyclic processes of
cell movement, including those responsible for regulating
polarity processes and the reorganization of the cytoskeleton, interaction with the ECM, and chemotactic signaling.
In this regard, the dynamics of formation, orientation, and
length of the primary cilium may serve as a switch by which
the cell can control its responsive potential during migratory events. Interneurons have been reported to repeatedly
display and remove their primary cilium during their stepwise centrosome or Golgi translocation and nucleokinesis
(Baudoin et al. 2012), and corneal epithelial cells uniquely
assemble a cilium in response to tissue injury that requires
a migratory response (Blitzer et al. 2011). Moreover, TGF

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http://bioscience.oxfordjournals.org

Acknowledgements
This work was supported by grants from the Lundbeck
Foundation; The Novo Nordisk Foundation; The Danish
Council for Independent Research (grant no. 1331-00254);
and the 2016 Excellence Program at the University of
Copenhagen, Denmark. We thank Johan Kolstrup and Peter
Satir, who have given permission for their scanning electron
micrograph to be used in the article. We apologize to those
investigators whose original work has been cited here only in
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Overview Articles

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