David J. Solecki

Activated Notch2 Signaling Inhibits Differentiation of Cerebellar Granule Neuron Precursors by Maintaining Proliferation

In the developing cerebellar cortex, granule neuron precursors (GNPs) proliferate and commence differentiation in a superficial zone, the external granule layer (EGL). The molecular basis of the transition from proliferating precursors to immature differentiating neurons remains unknown. Notch signaling is an evolutionarily conserved pathway regulating the differentiation of precursor cells of many lineages. Notch2 is specifically expressed in proliferating GNPs in the EGL. Treatment of GNPs with soluble Notch ligand Jagged1, or overexpression of activated Notch2 or its downstream target HES1, maintains precursor proliferation. The addition of GNP mitogens Jagged1 or Sonic Hedgehog (Shh) upregulates the expression of HES1, suggesting a role for HES1 in maintaining precursor proliferation.

New insights into the molecular mechanisms specifying neuronal polarity in vivo

The polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. Important progress has been made toward the identification of the molecular mechanisms regulating neuronal polarization using primarily in vitro approaches such as dissociated culture of rodent hippocampal neurons. The predominant view emerging from this paradigm is that neuronal polarization is initiated by intrinsic activation of signaling pathways underlying the initial break in neuronal symmetry that precedes the future asymmetric growth of the axon. Recent evidence shows that (i) axon-dendrite polarization is specified when neurons engage migration in vivo, (ii) that a kinase pathway defined by LKB1and SAD-kinases (Par4/Par1 dyad) is required for proper neuronal polarization in vivo and that (iii) extracellular cues can play an instructive role during neuronal polarization. Here, we review some of these recent results and highlight future challenges in the field including the determination of how extracellular cues control intracellular responses underlying neuronal polarization in vivo.

Siah Regulation of Pard3A Controls Neuronal Cell Adhesion During Germinal Zone Exit

Exiting the Birthplace In the developing mammalian brain, new neurons are not always born where they are needed. In order for immature neurons of the mouse cerebellum to leave their birthplace in the germinal zone and find their functional niche in the brain, the neurons need to migrate. Famulski et al. (p. 1834, published online 25 November; see the Perspective by Métin and Luccardini) now show that ubiquitin-mediated protein degradation regulates development of specific cell adhesions that the neurons need in order to exit their birthplace en route to their final functional location. A ubiquitination cascade regulates formation of cell adhesions that immature neurons require in the developing mouse brain. The brain’s circuitry is established by directed migration and synaptogenesis of neurons during development. Although neurons mature and migrate in specific patterns, little is known about how neurons exit their germinal zone niche. We found that cerebellar granule neuron germinal zone exit is regulated by proteasomal degradation of Pard3A by the Seven in Absentia homolog (Siah) E3 ubiquitin ligase. Pard3A gain of function and Siah loss of function induce precocious radial migration. Time-lapse imaging using a probe to measure neuronal cell contact reveals that Pard3A promotes adhesive interactions needed for germinal zone exit by recruiting the epithelial tight junction adhesion molecule C to the neuronal cell surface. Our findings define a Siah-Pard3A signaling pathway that controls adhesion-dependent exit of neuronal progenitors or immature neurons from a germinal zone niche.

mPar6α Controls Neuronal Migration

We review studies on the polarity of developing cerebellar granule, showing that the centrosome localizes to the pole of the neuron that extrudes the nascent axon, and the Rho GTPase Cdc42 (cell division cycle 42) activates the mPar6α/Par3 (Par for partitioning defective) complex to coordinate actin dynamics in the growth cone. Subsequently, mPar6α signaling controls the migration of immature granule neurons down the Bergmann glial fibers into the internal granule cell layer in which they establish synaptic connections.

Sticky situations: recent advances in control of cell adhesion during neuronal migration

The migration of neurons along glial fibers from a germinal zone (GZ) to their final laminar positions is essential for morphogenesis of the developing brain; aberrations in this process are linked to profound neurodevelopmental and cognitive disorders. During this critical morphogenic movement, neurons must navigate complex migration paths, propelling their cell bodies through the dense cellular environment of the developing nervous system to their final destinations. It is not understood how neurons can successfully migrate along their glial guides through the myriad processes and cell bodies of neighboring neurons. Although much progress has been made in understanding the substrates (Fishell G, Hatten ME: Astrotactin provides a receptor system for CNS neuronal migration. Development 1991, 113:755; Elias LA, Wang DD, Kriegstein AR: Gap junction adhesion is necessary for radial migration in the neocortex. Nature 2007, 448:901; Anton ES, Kreidberg JA, Rakic P: Distinct functions of alpha3 and alpha. (v) integrin receptors in neuronal migration and laminar organization of the cerebral cortex. Neuron 1999, 22:277; Anton ES, Marchionni MA, Lee KF, Rakic P: Role of GGF/neuregulin signaling in interactions between migrating neurons and radial glia in the developing cerebral cortex. Development 1997, 124:3501), guidance mechanisms (Polleux F, Whitford KL, Dijkhuizen PA, Vitalis T, Ghosh A: Control of cortical interneuron migration by neurotrophins and PI3-kinase signaling. Development 2002, 129:3147; Zhou P, et al.: Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 2007, 55:53; Renaud J, et al.: Plexin-A2 and its ligand, Sema6A, control nucleus-centrosome coupling in migrating granule cells. Nat Neurosci 2008, 11:440), cytoskeletal elements (Schaar BT, McConnell SK: Cytoskeletal coordination during neuronal migration. Proc Natl Acad Sci U S A 2005, 102:13652; Tsai JW, Bremner KH, Vallee RB: Dual subcellular roles for LIS1 and dynein in radial neuronal migration in live brain tissue. Nat Neurosci 2007, 10:970; Solecki DJ, et al.: Myosin II motors and F-actin dynamics drive the coordinated movement of the centrosome and soma during CNS glial-guided neuronal migration. Neuron 2009, 63:63), and post-translational modifications (Patrick GN, Zhou P, Kwon YT, Howley PM, Tsai LH: p35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway. J Biol Chem 1998, 273:24057; Suetsugu S, et al.: Regulation of actin cytoskeleton by mDab1 through N-WASP and ubiquitination of mDab1. Biochem J 2004, 384:1; Karakuzu O, Wang DP, Cameron S: MIG-32 and SPAT-3A are PRC1 homologs that control neuronal migration inCaenorhabditis elegans. Development 2009, 136:943) required for neuronal migration, we have yet to elucidate how neurons regulate their cellular interactions and adhesive specificity to follow the appropriate migratory pathways. Here I will examine recent developments in our understanding of the mechanisms controlling neuronal cell adhesion and how these mechanisms interact with crucial neurodevelopmental events, such as GZ exit, migration pathway selection, multipolar-to-radial transition, and final lamination.

Polarity transitions during neurogenesis and germinal zone exit in the developing central nervous system

During neural development, billions of neurons differentiate, polarize, migrate and form synapses in a precisely choreographed sequence. These precise developmental events are accompanied by discreet transitions in cellular polarity. While radial glial neural stem cells are highly polarized, transiently amplifying neural progenitors are less polarized after delaminating from their parental stem cell. Moreover, preceding their radial migration to a final laminar position neural progenitors re-adopt a polarized morphology before they embarking on their journey along a glial guide to the destination where they will fully mature. In this review, we will compare and contrast the key polarity transitions of cells derived from a neuroepithelium to the well-characterized polarity transitions that occur in true epithelia. We will highlight recent advances in the field that shows that neuronal progenitor delamination from germinal zone (GZ) niche shares similarities to an epithelial-mesenchymal transition. Moreover, studies in the cerebellum suggest the acquisition of radial migration and polarity in transiently amplifying neural progenitors share similarities to mesenchymal-epithelial transitions. Where applicable, we will compare and contrast the precise molecular mechanisms used by epithelial cells and neuronal progenitors to control plasticity in cell polarity during their distinct developmental programs.

New spin on an old transition: epithelial parallels in neuronal adhesion control

During histogenesis of the vertebrate central nervous system (CNS), neuronal progenitors must interact with germinal zone (GZ) niches, differentiate, and morphologically mature, and neurons must migrate to their final positions. The extrinsic cues that control neurogenesis, specify neurons, and guide their movement are relatively well understood. However, less is known about how neurons spatiotemporally modify cell-cell interactions and cell polarization to navigate through complex, distinct cellular environments during neuronal circuit formation. Here we examine the parallels between the mechanisms controlling epithelial morphogenesis and the cell adhesion events by which neural cells organize GZ niches and direct neuronal migration. We focus on the emerging relationship between neuronal adhesive interactions and conserved cell-polarity signaling cascades.

Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition

In the developing mammalian brain, differentiating neurons mature morphologically via neuronal polarity programs. Despite discovery of polarity pathways acting concurrently with differentiation, its unclear how neurons traverse complex polarity transitions or how neuronal progenitors delay polarization during development. We report that zinc finger and homeobox transcription factor-1 (Zeb1), a master regulator of epithelial polarity, controls neuronal differentiation by transcriptionally repressing polarity genes in neuronal progenitors. Necessity-sufficiency testing and functional target screening in cerebellar granule neuron progenitors (GNPs) reveal that Zeb1 inhibits polarization and retains progenitors in their germinal zone (GZ). Zeb1 expression is elevated in the Sonic Hedgehog (SHH) medulloblastoma subgroup originating from GNPs with persistent SHH activation. Restored polarity signaling promotes differentiation and rescues GZ exit, suggesting a model for future differentiative therapies. These results reveal unexpected parallels between neuronal differentiation and mesenchymal-to-epithelial transition and suggest that active polarity inhibition contributes to altered GZ exit in pediatric brain cancers. DOI: http://dx.doi.org/10.7554/eLife.12717.001

Alix-mediated assembly of the actomyosin–tight junction polarity complex preserves epithelial polarity and epithelial barrier

Maintenance of epithelial cell polarity and epithelial barrier relies on the spatial organization of the actin cytoskeleton and proper positioning/assembly of intercellular junctions. However, how these processes are regulated is poorly understood. Here we reveal a key role for the multifunctional protein Alix in both processes. In a knockout mouse model of Alix, we identified overt structural changes in the epithelium of the choroid plexus and in the ependyma, such as asymmetrical cell shape and size, misplacement and abnormal beating of cilia, blebbing of the microvilli. These defects culminate in excessive cell extrusion, enlargement of the lateral ventricles and hydrocephalus. Mechanistically, we find that by interacting with F-actin, the Par complex and ZO-1, Alix ensures the formation and maintenance of the apically restricted actomyosin–tight junction complex. We propose that in this capacity Alix plays a role in the establishment of apical–basal polarity and in the maintenance of the epithelial barrier.

Neuronal migration illuminated: a look under the hood of the living neuron.

During vertebrate brain development, migration of neurons from the germinal zones to their final laminar positions is essential to establish functional neural circuits1-3. Whereas key insights into neuronal migration initially came from landmark studies identifying the genes mutated in human cortical malformations4, cell biology has recently greatly advanced our understanding of how cytoskeletal proteins and molecular motors drive the morphogenic cell movements that build the developing brain. This Commentary & View reviews recent studies examining the role of the molecular motors during neuronal migration and critically examines current models of acto-myosin function in the two-step neuronal migration cycle. Given the apparent emerging diversity of neuronal sub-type cytoskeletal organizations, we propose that two approaches must be taken to resolve differences between the current migration models: the mechanisms of radial and tangential migration must be compared and the loci of tension generation, migration substrates, and sites of adhesion dynamics must be precisely examined in an integrated manner.