Little is known about the architecture of cellular microenvironments that support stem and precursor cells during tissue development. Although adult stem cell niches are organized by specialized ...supporting cells, in the developing cerebral cortex, neural stem/precursor cells reside in a neurogenic niche lacking distinct supporting cells. Here, we find that neural precursors themselves comprise the niche and regulate their own development. Precursor-precursor contact regulates β-catenin signaling and cell fate. In vivo knockdown of N-cadherin reduces β-catenin signaling, migration from the niche, and neuronal differentiation in vivo. N-cadherin engagement activates β-catenin signaling via Akt, suggesting a mechanism through which cells in tissues can regulate their development. These results suggest that neural precursor cell interactions can generate a self-supportive niche to regulate their own number.
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► Cortical ventricular zone neural precursors exhibit β-catenin signaling ► N-cadherin maintains β-catenin signaling in cortical precursors ► N-cadherin regulates neuronal differentiation and cell cycle exit via β-catenin ► N-cadherin signals through Akt and phosphor-Ser552 of β-catenin
The generation and differentiation of neurons during development requires coordination of intercellular interactions with spatio-temporal changes in gene expression. To examine the role of adhesion ...in cerebral cortical development, we overexpressed full-length cadherin and dominant-negative truncated cadherin in mouse cortical precursors. Full-length cadherin allowed for the maintenance of cell contact between daughter cells following cell division while dominant-negative cadherin decreased cell contact. Paradoxically, both cadherin isoforms inhibited precursor proliferation, induced premature neuronal differentiation, and inhibited β-catenin dependent signaling. Furthermore, alteration of cadherin or β-catenin function led to additional changes in precursor identity and division symmetry as demonstrated by altered expression of the radial glial marker, Pax6, and the intermediate precursor marker, Tbr2. Moreover, clonal analysis demonstrated asymmetric distribution of Tbr2 following precursor mitosis. Together, these results show that cadherins affect neural precursor fate determination through a cell-autonomous regulation of catenin signaling distinct from cadherin adhesive function.
Little is known about the architecture of cellular microenvironments that support stem and precursor cells during tissue development. Although adult stem cell niches are organized by specialized ...supporting cells, in the developing cerebral cortex, neural stem/precursor cells reside in a neurogenic niche lacking distinct supporting cells. Here, we find that neural precursors themselves comprise the niche and regulate their own development. Precursor-precursor contact regulates b-catenin signaling and cell fate. In vivo knockdown of N-cadherin reduces b-catenin signaling, migration from the niche, and neuronal differentiation in vivo. N-cadherin engagement activates b-catenin signaling via Akt, suggesting a mechanism through which cells in tissues can regulate their development. These results suggest that neural precursor cell interactions can generate a self-supportive niche to regulate their own number. Highlights - Cortical ventricular zone neural precursors exhibit b-catenin signaling N-cadherin maintains b-catenin signaling in cortical precursors N-cadherin regulates neuronal differentiation and cell cycle exit via b-catenin N-cadherin signals through Akt and phosphor-Ser552 of b-catenin
Cellular interactions are important for the development and maintenance of tissue structural integrity. In the developing neuroepithelium, the adherens junction proteins, N-cadherin and β-catenin, ...are highly enriched at the apical surface of the proliferative ventricular zone and have been suggested to have critical functions in ensuring the proper development of the neocortex. We examine the role that N-cadherin mediated adhesion and Wnt/β-catenin signaling plays during neocortical development with special emphasis on neural precursor proliferation and cell fate specification. We find that adhesion and signaling mediated by N-cadherin and β-catenin are intimately linked and control the decision of a neural precursor cell to proliferate or differentiate. Furthermore, we find that there may be multiple levels of the regulation of neural precursor proliferation and differentiation mediated by N-cadherin and β-catenin involving the interaction with components of multiple signaling pathways. The insights provided by this thesis will lead to a greater understanding of cerebral cortical development and provide additional avenues of research to investigate the specification of the various cells types found in the cortex.
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