NIH Research Festival
Primary microcephaly and microcephalic primordial dwarfism (MPD) are a spectrum of genetic disorders characterized by reduced brain size and, in MPD, reduced body size. Most identified primary microcephaly and MPD genes function at centrosomes, kinetochores or in DNA damage response (DDR). The mechanisms underlying microcephaly, such as reduced cell proliferation or increased apoptosis, have predominantly been inferred from cell culture phenotypes; animal models are less common, but may reveal additional neurodevelopmental functions for these genes. We are systematically screening mutant and RNAi lines of microcephaly and MPD gene orthologs in Drosophila melanogaster to establish animal models and thus shed light upon the mechanisms underlying microcephaly. Nopo is the ortholog of the MPD gene TRAIP and encodes an E3 ubiquitin ligase that regulates DDR pathways. We found that nopo mutants have major defects in the development of the mushroom body (MB), which is a brain region critical for memory formation. Spc105r is the ortholog of the human microcephaly gene KNL1 and encodes a critical kinetochore-associated protein. We found that knockdown of Spc105r in neural stem cells completely disrupts organization of the central brain, but not the optic lobes; knockdown in post-mitotic neurons is even more severe, suggesting a novel non-mitotic role for kinetochore proteins in neural development. These exciting results suggest that, as we continue to screen for and characterize microcephaly and MPD mutant and knockdown phenotypes in D. melanogaster, we are likely to uncover additional novel functions and establish a better understanding of the mechanisms underlying these diseases.
Scientific Focus Area: Developmental Biology
This page was last updated on Friday, March 26, 2021