Elucidating the major role of minor splicing during neurodevelopment in health and diseases

• Applicant: Dr. Oriane Mauger, Ph.D.
• Subject Area: Developmental Neurobiology ; General Genetics and Functional Genome Biology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568819061

Alternative splicing profoundly shapes the molecular identity of cells throughout tissue development. It is notably crucial for the development of the central nervous system to ensure various processes such as neural progenitor stock turnover, neuronal differentiation or specification. Two large ribonucleoproteic complexes execute splicing, the major and the minor spliceosomes. The former is in charge of the vast majority of introns, the latter of only ~850 minor introns. Recent findings tend to revisit this dogma: expression of a wide repertoire of snRNA variants - initially considered as redundant - would actually multiply major spliceosome entities that could exhibit subtle differences in premRNA substrate specificity. Hence, the minor spliceosome might represent an extreme form of such variant spliceosomes. This new vision is supported by the breakthrough discovery of pathogenic variants in more and more snRNA genes, which all cause severe neurodevelopmental defects, without, to date, a clear understanding of the underlying pathophysiological mechanisms. Here, we want to take advantage of the study of very rare microcephalic osteodysplastic growth restriction genetic syndromes, caused by mutations in the U4atac snRNA minor spliceosome component, to investigate neuronal differentiation splicing specificities. Our preliminary data already reveal that dysfunction of U4atac leads to both minor and major splicing alterations, unveiling the importance of spliceosome repertoire homeostasis. To tackle this project, we will use a set of complementary models including human iPSC-derived neurons, zebrafish, mouse, and transcriptomic and proteomic approaches to study 1) the pattern of expression and activity of the spliceosomes during neurodevelopment; 2) the consequences of the dysfunction of minor splicing from the molecular to the cellular and tissue levels; 3) the splicing alterations that contribute the most to microcephaly and whether they can be reverted.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partners: Dr. Marion Delous, Ph.D.; Professorin Sylvie Mazoyer, Ph.D.