Planar cell polarity signaling in neural development
Introduction
Planar cell polarity (PCP) refers to the organization of cell sheets in the tangential plane, along an anatomical axis perpendicular to the familiar, apicobasal cell polarity. Although PCP and its regulation have been scrutinized in Drosophila for decades [1, 2, 3], studies of PCP in vertebrates is recent, especially in neural development [4]. Since the nervous system derives from an epithelial neural plate, the involvement of PCP signaling in the neuroepithelium appears a posteriori quite trivial. What was less predictable, however, is that PCP signaling also plays crucial roles in axonal guidance, ependymal ciliogenesis, dendrite maturation, neural stem cell regulation, and even neuron survival, thus making it a major player.
Section snippets
Lessons from Drosophila: core PCP genes
In flies, the main readout of PCP is the organization of hairs on the wing [2], and to a lesser extent ommadia rotation [5], orientation of body appendages [6] and somatosensory organ precursor division [7, 8•]. Pupal wing cells are decorated with prehairs that develop as an actin-rich bundle before being incorporated in the cuticle. Normally, hairs develop at the distal cell side and point distally, and screenings for hair abnormalities led to identification of ‘core’ PCP genes Frizzled,
PCP signaling relies on a polarized partition of protein complexes
The consensus view is that PCP is mediated by transient asymmetric expression of surface membrane complexes in different sectors of the adherens junction (AJ) belt (Figure 1). In the wing, Flamingo is present symmetrically, whereas Frizzled and Van Gogh are targeted to opposing junctional domains, Frizzled to the distal side — where the hair is located — and Van Gogh to proximal side (Figure 2). Interactions mediated by these complexes propagate asymmetric signals from cell to cell, a distal signal
Relationship between PCP and anatomical axes
Polarized expression of Frizzled and Van Gogh, with symmetric expression of Flamingo, can be schematized as elementary vectors F–V (Figure 2). One interesting issue is how are those F–V vectors oriented with respect to anatomically defined axes? In some instances, such as the wing, F–V vectors are parallel to the proximodistal axis. They are also parallel to the direction of the mitotic spindle in asymmetric cell division in sensory organs (Figure 3) [15]. On the other hand, in the cochlea
Expression of core PCP genes during brain development in mice
Human and mice have 10 Frizzled (Fzd1–10), four Prickle (Prickle1–4), three Dishevelled (Dvl1–3), two Van Gogh (Vangl1 and 2) and three Flamingo/starry night orthologs (Celsr1–3, ‘cadherin EGF laminin seven-pass receptors 1–3’). Orthologs are also described in zebrafish and Xenopus, sometimes under different names, and some in duplicate because of partial tetraploidy; for example, there are two Celsr1 (1a and 1b) in zebrafish.
PCP gene orthologs are expressed during brain development [16].
PCP, the organization of inner ear receptor cells, and neural tube closure
Actin stereocilia on the apical surface of cochlear receptor cells form a ‘V’ centered on a primary kinocilium at the tip. Organization of stereocilia is affected in mice with mutations of Celsr1 [17], Vangl2 [18, 19] and Fzd3 and 6 [20]. Analysis of the planar distribution of PCP molecules suggests that a PCP signal transversal to the cochlear axis governs the position and orientation of the kinocilium, which in turn affects orientation of stereocilia [21]. The organization of stereocilia in
PCP, neural stem cell biology, and neuronal migration and maturation
Expression patterns suggest roles of Celsr1 in NSC, and Celsr2–3 in brain maturation. This ‘dual’ system was investigated during caudal migration of facial branchiomotor (FBM) neurons from rhombomere (r)4, where they are generated, to r6 where they settle and form nucleus VII. Loss of function of Celsr1 in NSC results into abnormal migration of daughter FBM neurons, in rostral, lateral and caudal directions. This phenotype is not seen when Celsr1 is conditionally inactivated in FBM neurons
PCP and brain wiring
Mutations of Celsr3 and Fzd3 generate similar axonal guidance defects along the whole neuraxis, with prominent wiring abnormalities in the spinal cord, brainstem, mid- and forebrain [13, 24, 37, 38••], indicating that PCP molecules have wider roles than other axonal guidance systems which have a more local or restricted action [39]. Defective non-canonical Wnt signaling was proposed to account for wiring defects in Fzd3 mutants [13]. On the other hand, region-specific ablation of Celsr3
PCP and ciliogenesis
PCP governs cilia development in epidermis of larval Xenopus. Morpholino downregulation of Dishevelled1-3, Inturned, and Fuzzy affects the actin cytoskeleton and apical docking of ciliary basal bodies [40•]. Recently, Celsr2 and Celsr3 were shown to be required for the development of ependymal cilia in mice [41••]. Combined loss of Celsr2 and Celsr3 severely impairs ciliogenesis, leading to defective flow of cerebrospinal fluid and lethal hydrocephalus. Although differentiation of ependymal
Conclusion: towards a unifying view?
Evidence is accumulating that a main effect of PCP signaling is to regulate actin dynamics, which is known — from studies in brain development and other fields — to impact on directional growth cone navigation [44], basal body cilia docking, neuronal migration [45], dendrite growth and maintenance [46], and on directed mitotic division, at least in oocytes [47•]. Key questions remain. We do not know whether extracellular signals are involved in PCP signaling, nor the links between PCP proteins and
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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