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 comparative study of nucleostemin family members in zebrafish reveals specific roles in ribosome biogenesis

Nucleostemin (NS) is an essential protein for the growth and viability of developmental stem cells. Its functions are multi-faceted, including important roles in ribosome biogenesis and in the p53-induced apoptosis pathway. While NS has been well studied, the functions of its family members GNL2 and GNL3-like (GNL3L) remain relatively obscure despite a high degree of sequence and domain homology. Here, we use zebrafish lines carrying mutations in the ns family to compare and contrast their functions in vertebrates. We find the loss of zebrafish ns or gnl2 has a major impact on 60S large ribosomal subunit formation and/or function due to cleavage impairments at distinct sites of pre-rRNA transcript. In both cases this leads to a reduction of total protein synthesis. In contrast, gnl3l loss shows relatively minor rRNA processing delays that ultimately have no appreciable effects on ribosome biogenesis or protein synthesis. However, the loss of gnl3l still results in p53 stabilization, apoptosis, and lethality similarly to ns and gnl2 loss. The depletion of p53 in all three of the mutants led to partial rescues of the morphological phenotypes and surprisingly, a rescue of the 60S subunit collapse in the ns mutants. We show that this rescue is due to an unexpected effect of p53 loss that even in wild type embryos results in an increase of 60S subunits. Our study presents an in-depth description of the mechanisms through which ns and gnl2 function in vertebrate ribosome biogenesis and shows that despite the high degree of sequence and domain homology, gnl3l has critical functions in development that are unrelated to the ribosome

Insm1 Induces Neural Progenitor Delamination in Developing Neocortex via Downregulation of the Adherens Junction Belt-Specific Protein Plekha7

Summary Delamination of neural progenitor cells (NPCs) from the ventricular surface is a crucial prerequisite to form the subventricular zone, the germinal layer linked to the expansion of the mammalian neocortex in development and evolution. Here, we dissect the molecular mechanism by which the transcription factor Insm1 promotes the generation of basal progenitors (BPs). Insm1 protein is most highly expressed in newborn BPs in mouse and human developing neocortex. Forced Insm1 expression in embryonic mouse neocortex causes NPC delamination, converting apical to basal radial glia. Insm1 represses the expression of the apical adherens junction belt-specific protein Plekha7. CRISPR/Cas9-mediated disruption of Plekha7 expression suffices to cause NPC delamination. Plekha7 overexpression impedes the intrinsic and counteracts the Insm1-induced, NPC delamination. Our findings uncover a novel molecular mechanism underlying NPC delamination in which a BP-genic transcription factor specifically targets the integrity of the apical adherens junction belt, rather than adherens junction components as such

The developmental stage of the medulloblastoma cell-of-origin restricts Hedgehog pathway usage and drug sensitivity

Sonic Hedgehog (SHH) medulloblastoma originates from the cerebellar granule neuron progenitor (CGNP) lineage that depends on Hedgehog signaling for its perinatal expansion. While SHH tumors exhibit overall deregulation of this pathway, they also show patient age-specific aberrations. To investigate if the developmental stage of the CGNP can account for these age-specific lesions, we analyzed developing murine CGNP transcriptomes and observed highly dynamic gene expression as function of age. Cross-species comparison with human SHH medulloblastoma showed partial maintenance of these expression patterns, and highlighted low primary cilium expression as hallmark of infant medulloblastoma and early embryonic CGNPs. This coincided with reduced responsiveness to upstream Shh pathway component Smoothened, while sensitivity to downstream components Sufu and Gli was retained. Together, these findings can explain the preference for SUFU mutations in infant medulloblastoma and suggest that drugs targeting the downstream SHH pathway will be most appropriate for infant patients

The Golgi apparatus in polarized neuroepithelial stem cells and their progeny: Canonical and noncanonical features

Neurons forming the central nervous system are generated by neural stem and progenitor cells, via a process called neurogenesis (Gö}tz and Huttner, Nat Rev Mol Cell Biol, 6:777--788, 2005). In this book chapter, we focus on neurogenesis in the dorsolateral telencephalon, the rostral-most region of the neural tube, which contains the part of the central nervous system that is most expanded in mammals (Borrell and Reillo, Dev Neurobiol, 72:955--971, 2012; Wilsch-Br{äuninger et al., Curr Opin Neurobiol 39:122--132, 2016). We will discuss recent advances in the dissection of the cell biological mechanisms of neurogenesis, with particular attention to the organization and function of the Golgi apparatus and its relationship to the centrosome