The Symmetry of Neural Stem Cell and Progenitor Divisions in the Vertebrate Brain

Robust brain development requires the tight coordination between tissue growth, neuronal differentiation and stem cell maintenance. To achieve this, neural stem cells need to balance symmetric proliferative and terminal divisions with asymmetric divisions. In recent years, the unequal distribution of certain cellular components in mitosis has emerged as a key mechanism to regulate the symmetry of division, and the determination of equal and unequal sister cell fates. Examples of such components include polarity proteins, signaling components, and cellular structures such as endosomes and centrosomes. In several types of neural stem cells, these factors show specific patterns of inheritance that correlate to specific cell fates, albeit the underlying mechanism and the potential causal relationship is not always understood. Here, we review these examples of cellular neural stem and progenitor cell asymmetries and will discuss how they fit into our current understanding of neural stem cell function in neurogenesis in developing and adult brains. We will focus mainly on the vertebrate brain, though we will incorporate relevant examples from invertebrate organisms as well. In particular, we will highlight recent advances in our understanding of the complexities related cellular asymmetries in determining division mode outcomes, and how these mechanisms are spatiotemporally regulated to match the different needs for proliferation and differentiation as the brain forms

Frizzled-3a and Wnt-8b genetically interact during forebrain commissural formation in embryonic zebrafish

The commissural plate forms the rostral surface of the embryonic vertebrate forebrain and provides a cellular substrate for forebrain commissural axons. We have previously reported that the Wnt receptor frizzled-3a (fzd3a) restricts the expression of the chemorepulsive guidance ligand slit2 to a discrete domain of neuroepithelial cells in the commissural plate of embryonic zebrafish. Loss of Fzd3a function perturbed slit2 expression and disrupted the formation of glial bridges which guide the formation of forebrain commissures. We now show that Wnt8b is also necessary for anterior commissural formation as well as for patterning of slit2 expression at the midline. Knock down of Wnt8b produced the same phenotype as loss of Fzd3a which suggested that these genes were acting together to regulate axon guidance. Simultaneous sub-threshold knock down of both Fzd3a and Wnt8b led to a greater than additive increase in the penetrance of the mutant phenotype which indicated that these two genes were indeed interacting. We have shown here that Fzd3a/Wnt8b signaling is essential for normal patterning of the commissural plate and that loss-of-function in either receptor or ligand causes Slit2-dependent defects in glial bridge morphology which indirectly attenuated axon midline crossing in the embryonic vertebrate forebrain. (C) 2013 Elsevier B.V. All rights reserved

Modular reorganization of the global network of gene regulatory interactions during perinatal human brain development.

BACKGROUND During early development of the nervous system, gene expression patterns are known to vary widely depending on the specific developmental trajectories of different structures. Observable changes in gene expression profiles throughout development are determined by an underlying network of precise regulatory interactions between individual genes. Elucidating the organizing principles that shape this gene regulatory network is one of the central goals of developmental biology. Whether the developmental programme is the result of a dynamic driven by a fixed architecture of regulatory interactions, or alternatively, the result of waves of regulatory reorganization is not known. RESULTS Here we contrast these two alternative models by examining existing expression data derived from the developing human brain in prenatal and postnatal stages. We reveal a sharp change in gene expression profiles at birth across brain areas. This sharp division between foetal and postnatal profiles is not the result of pronounced changes in level of expression of existing gene networks. Instead we demonstrate that the perinatal transition is marked by the widespread regulatory rearrangement within and across existing gene clusters, leading to the emergence of new functional groups. This rearrangement is itself organized into discrete blocks of genes, each targeted by a distinct set of transcriptional regulators and associated to specific biological functions. CONCLUSIONS Our results provide evidence of an acute modular reorganization of the regulatory architecture of the brain transcriptome occurring at birth, reflecting the reassembly of new functional associations required for the normal transition from prenatal to postnatal brain development

A quantitative characterization of early neuron generation in the developing zebrafish telencephalon

The adult brain is made up of anatomically and functionally distinct regions with specific neuronal compositions. At the root of this neuronal diversity are neural stem and progenitor cells (NPCs) that produce many neurons throughout embryonic development. During development, NPCs switch from initial expanding divisions to neurogenic divisions, which marks the onset of neurogenesis. Here, we aimed to understand when NPCs switch division modes to generate the first neurons in the anterior-most part of the zebrafish brain, the telencephalon. To this end, we used the deep learning-based segmentation method Cellpose and clonal analysis of individual NPCs to assess the production of neurons by NPCs in the first 24 h of zebrafish telencephalon development. Our results provide a quantitative atlas detailing the production of telencephalic neurons and NPC division modes between 14 and 24 h postfertilization. We find that within this timeframe, the switch to neurogenesis is gradual, with considerable heterogeneity in individual NPC neurogenic potential and division rates. This quantitative characterization of initial neurogenesis in the zebrafish telencephalon establishes a basis for future studies aimed at illuminating the molecular mechanisms and regulators of early neurogenesis.</p

A quantitative characterization of early neuron generation in the developing zebrafish telencephalon

The adult brain is made up of anatomically and functionally distinct regions with specific neuronal compositions. At the root of this neuronal diversity are neural stem and progenitor cells (NPCs) that produce many neurons throughout embryonic development. During development, NPCs switch from initial expanding divisions to neurogenic divisions, which marks the onset of neurogenesis. Here, we aimed to understand when NPCs switch division modes to generate the first neurons in the anterior-most part of the zebrafish brain, the telencephalon. To this end, we used the deep learning-based segmentation method Cellpose and clonal analysis of individual NPCs to assess the production of neurons by NPCs in the first 24 h of zebrafish telencephalon development. Our results provide a quantitative atlas detailing the production of telencephalic neurons and NPC division modes between 14 and 24 h postfertilization. We find that within this timeframe, the switch to neurogenesis is gradual, with considerable heterogeneity in individual NPC neurogenic potential and division rates. This quantitative characterization of initial neurogenesis in the zebrafish telencephalon establishes a basis for future studies aimed at illuminating the molecular mechanisms and regulators of early neurogenesis.</p

SP8 transcriptional regulation of Cyclin D1 during mouse early corticogenesis

Multiple signals control the balance between proliferation and differentiation of neural progenitor cells during corticogenesis. A key point of this regulation is the control of G1 phase length, which is regulated by the Cyclin/Cdks complexes. Using genome-wide chromatin immunoprecipitation assay and mouse genetics, we have explored the transcriptional regulation of Cyclin D1 (Ccnd1) during the early developmental stages of the mouse cerebral cortex. We found evidence that SP8 binds to the Ccnd1 locus on exon regions. In vitro experiments show SP8 binding activity on Ccnd1 gene 3′-end, and point to a putative role for SP8 in modulating PAX6-mediated repression of Ccnd1 along the dorso-ventral axis of the developing pallium, creating a medialLow-lateralHigh gradient of neuronal differentiation. Activation of Ccnd1 through the promoter/5′-end of the gene does not depend on SP8, but on βcatenin (CTNNB1). Importantly, alteration of the Sp8 level of expression in vivo affects Ccnd1 expression during early corticogenesis. Our results indicate that Ccnd1 regulation is the result of multiple signals and that SP8 is a player in this regulation, revealing an unexpected and potentially novel mechanism of transcriptional activation