CDH2 restricts notch and GLI1-Mediated SHH signaling to ensure proper neocortical development
- Autores: DAVID DE AGUSTÍN DURÁN
- Directores de la Tesis: Cristina Gil Sanz (dir. tes.)
- Lectura: En la Universitat de València ( España ) en 2025
- Idioma: español
- Tribunal Calificador de la Tesis: Víctor Borrell Franco (presid.), Isabel Martínez Garay (secret.), Soraia Barao (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina y Biotecnología por la Universitat de València (Estudi General)
- Materias:
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- Resumen
The neocortex is the most recent acquisition of the mammalian brain, accomplishing a wide range of sophisticated tasks, such as sensory perception, motor integration, cognition, complex though, reasoning and language, among others. Many molecular players, including cell-cell adhesion molecules (CCAMs), are known to drive its formation through tightly regulated mechanisms that, when perturbed, lead to neurodevelopmental disorders. While genetic inactivation in the dorsal telencephalon of other adherens junction (AJ)-associated proteins forces neural progenitors to prematurely exit cell cycle, the loss of cadherin-2 (Cdh2), also located within AJs, enhances progenitor proliferation throughout the whole nascent neocortex, leading to dramatic neocortical disorganization and overproduction of projection neurons (PNs) typical of the upper neocortical layers. The fact that neocorticogenesis is affected in opposite manners depending on how AJs are disrupted could indicate the existence of further roles beyond cell adhesion for specific CCAMs, such as Cdh2, that have remained largely obscure.
By performing gene expression analysis through bulk RNA sequencing, quantitative PCR, fluorescent in situ hybridization and immunohistochemistry in wildtype and cortical Cdh2 knockout embryos, we have identified differentially expressed genes associated with Notch and Sonic Hedgehog (Shh) pathways, including Gli1 transcription factor. Functional experiments antagonizing these signaling pathways through different in vitro and in vivo strategies partially rescue the overproliferation phenotype, suggesting a previously unknown adhesion-independent role of Cdh2 in the control of molecular mechanisms governing mammalian corticogenesis. Besides, Gli1 in vivo overexpression triggers the generation of proliferating progenitors in basal cortical locations that, eventually, predominantly give rise to upper-layer PNs, while causing downregulation of Cdh2 expression. These alterations are rescued by Cdh2 overexpression, pointing towards the existence of a mutually repressive Cdh2-Gli1 axis of key importance for the regulation of neural progenitors in terms of location, proliferation rates and cell fate during neocortical development. Finally, behavioural testing in early born mutant mice has revealed autism spectrum disorder (ASD)-like alterations upon the deletion of both Cdh2 and AJ-associated protein Afadin. In adult Afadin cKO mice, with similar cortical aberrations, we have unveiled the existence of important sociability alterations. Together, our findings contribute to reach a better understanding of how cell adhesion molecules govern neocortical development through molecular mechanisms that, when perturbed, cause behavioural deficits, and might help to provide new insights into ASD pathogenesis.
