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Cooperation between Dmrta2/5 and Emx2 transcription factors during cortical development

par Anirudhan, Jithu
Président du jury Vanhamme, Luc
Promoteur Bellefroid, Eric
Publication Non publié, 2024-06-06

Thèse de doctorat

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Résumé :

A highly evolved neocortex is associated with higher-order cognitive abilities humans possess. Thus, it is imperative to understand how the human cortex develops and its associated diseases. A complex network of transcription factors orchestrates the patterning of the cortex. Among them, Dmrt5 and Emx2 are evolutionarily conserved and are expressed early and similarly in the developing cortex. Interestingly, either of their deletions results in strikingly similar phenotypes and their compound deletion leads to an adverse phenotype, suggesting they cooperate during cortical development. During the first part of my PhD, I tried to understand the mechanisms at the basis of their cooperative function using mouse transgenics, bulk RNA sequencing, chromatin immunoprecipitation followed by sequencing and mass spectrometry-based methods. Our result suggests that their deletion perturbs a similar set of gene regulatory networks. Unexpectedly, their common direct targets are rather limited, but all encode important regulators of cortical fate. Exploration of their protein partners through mass spectrometry-based methods points to possible mechanisms contributing to their functional disparity, wherein they utilise a different set of interactors that confers their distinct functional properties. In the second part of my thesis, I also explored the unique role played by Dmrt5 in the development of the choroid plexus tissue, a brain-associated epithelial-endothelial convolute tissue that is involved in most of the cerebrospinal fluid production. The choroid plexus epithelium derives from the neuroepithelial tissue, which selectively expresses Dmrt5 as opposed to Emx2. Dmrt5 conditional ablation in the medial pallium does not result in any identifiable specification defects of the choroid plexus. Yet, mice in which Dmrt5 is conditionally deleted postnatally develop hydrocephalous, a condition often linked with defective choroid plexus function. Results obtained suggest that this phenotype results from a compromised cytoarchitecture.