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Soluble CPG15 expressed during early development rescues cortical progenitors from apoptosis.

ABSTRACT: The balance between proliferation and apoptosis is critical for proper development of the nervous system. Yet, little is known about molecules that regulate apoptosis of proliferative neurons. Here we identify a soluble, secreted form of CPG15 expressed in embryonic rat brain regions undergoing rapid proliferation and apoptosis, and show that it protects cultured cortical neurons from apoptosis by preventing activation of caspase 3. Using a lentivirus-delivered small hairpin RNA, we demonstrate that endogenous CPG15 is essential for the survival of undifferentiated cortical progenitors in vitro and in vivo. We further show that CPG15 overexpression in vivo expands the progenitor pool by preventing apoptosis, resulting in an enlarged, indented cortical plate and cellular heterotopias within the ventricular zone, similar to the phenotypes of mutant mice with supernumerary forebrain progenitors. CPG15 expressed during mammalian forebrain morphogenesis may help balance neuronal number by countering apoptosis in specific neuroblasts subpopulations, thus influencing final brain size and shape.

SUBMITTER: Putz U

PROVIDER: S-EPMC3075944 | biostudies-literature | 2005 Mar

REPOSITORIES: biostudies-literature

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Soluble CPG15 expressed during early development rescues cortical progenitors from apoptosis.

Putz Ulrich U Harwell Corey C Nedivi Elly E

Nature neuroscience 20050213 3

The balance between proliferation and apoptosis is critical for proper development of the nervous system. Yet, little is known about molecules that regulate apoptosis of proliferative neurons. Here we identify a soluble, secreted form of CPG15 expressed in embryonic rat brain regions undergoing rapid proliferation and apoptosis, and show that it protects cultured cortical neurons from apoptosis by preventing activation of caspase 3. Using a lentivirus-delivered small hairpin RNA, we demonstrate ...[more]

PMID: 15711540

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Project description:The central nervous system (CNS) develops from a heterogeneous pool of neural stem and progenitor cells (NSPC), the underlying differences among which are poorly understood. The study of NSPC would be greatly facilitated by the identification of additional proteins that mediate their function and that would distinguish amongst different progenitor populations.To identify membrane and membrane-associated proteins expressed by NSPC, we used a proteomics approach to profile NSPC cultured as neurospheres (NS) isolated from the murine cortex during a period of neurogenesis (embryonic day 11.5, E11.5), as compared to NSPC isolated at a peak of gliogenesis (postnatal day 1, P0) and to differentiated E11.5 NS. 54 proteins were identified with high expression in E11.5 NS, including the TrkC receptor, several heterotrimeric G proteins, and the Neogenin receptor. 24 proteins were identified with similar expression in E11.5 and P0 NS over differentiated E11.5 NS, and 13 proteins were identified with high expression specifically in P0 NS compared to E11.5 NS. To illustrate the potential relevance of these identified proteins to neural stem cell biology, the function of Neogenin was further studied. Using Fluorescence Activated Cell Sorting (FACS) analysis, expression of Neogenin was associated with a self-renewing population present in both E11.5 and adult subventricular zone (SVZ) NS but not in P0 NS. E11.5 NS expressed a putative Neogenin ligand, RGMa, and underwent apoptosis when exposed to a ligand-blocking antibody.There are fundamental differences between the continuously self-renewing and more limited progenitors of the developing cortex. We identified a subset of differentially expressed proteins that serve not only as a set of functionally important proteins, but as a useful set of markers for the subsequent analysis of NSPC. Neogenin is associated with the continuously self-renewing and neurogenic cells present in E11.5 cortical and adult SVZ NS, and the Neogenin/RGMa receptor/ligand pair may regulate cell survival during development.

Project description:The development of precise neural circuits in the brain requires spontaneous patterns of neural activity prior to functional maturation. In the rodent cerebral cortex patchwork and wave patterns of activity develop in somatosensory and visual regions, respectively, and are present at birth. However, whether such activity patterns occur in non-eutherian mammals, as well as when and how they arise during development remain open questions relevant to understand brain formation in health and disease. Since the onset of patterned cortical activity is challenging to study prenatally in eutherians, here we offer a new approach in a minimally invasive manner using marsupial dunnarts, whose cortex forms postnatally. We discovered similar patchwork and travelling waves in the dunnart somatosensory and visual cortices at stage 27 (equivalent to newborn mice), and examined progressively earlier stages of development to determine their onset and how they first emerge. We observed that these patterns of activity emerge in a region-specific and sequential manner, becoming evident as early as stage 24 in somatosensory and stage 25 in visual cortices (equivalent to embryonic day 16 and 17, respectively, in mice), as cortical layers establish and thalamic axons innervate the cortex. In addition to sculpting synaptic connections of existing circuits, evolutionarily conserved patterns of neural activity could therefore help regulate early events in cortical development.Significance statementRegion-specific patterns of neural activity are present at birth in rodents and are thought to refine synaptic connections during critical periods of cerebral cortex development. Marsupials are born much more immature than rodents, allowing the investigation of how these patterns arise in vivo. We discovered that cortical activity patterns are remarkably similar in marsupial dunnarts and rodents, and that they emerge very early, before cortical neurogenesis is complete. Moreover, they arise from the outset in different patterns specific to somatosensory and visual areas (i.e., patchworks and waves) indicating they may also play evolutionarily conserved roles in cortical regionalization during development.

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Soluble CPG15 expressed during early development rescues cortical progenitors from apoptosis.

Publications

Soluble CPG15 expressed during early development rescues cortical progenitors from apoptosis.

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