This proposal seeks to address the molecular mechanisms of autosomal recessive primary microcephaly (MCPH), a disorder characterized by small brain size and reduced life expectancy. Specifically, it focuses on the two most commonly mutated genes in MCPH patients, Abnormal Spindle (Asp) and WD Repeat-Containing Protein 62 (WDR62). A comprehensive, mentored training regimen in both research and career development has been established in order to ensure success as an independent investigator. First, this proposal uses an innovative approach in Drosophila melanogaster in order to elucidate the molecular mechanisms of the disorder, focusing on high resolution analysis of brains at the cell and tissue level using novel genetic & imaging methods. This phase will require training in fly neurobiology, and a co-mentor who is a leading expert in the field has been established to serve in this role. Secondly, a novel nuclear function for Asp & WDR62 will be investigated as the underlying mechanism of MCPH, combining previous graduate training in fly chromatin biology and gene expression with new training in next-generation sequencing technologies. Both the fly neurobiology and investigation into the nuclear function of these proteins will build towards the long term goals of the proposed research, which is to define an `MCPH gene network' that collectively contributes to proper brain size. This will begin during the mentored phase of the award by generating tools & reagents that will be critical for success during the independent phase. A genetic modifier screen in the Asp and WDR62 mutant background will also be carried out to identify candidate genes in the MCPH gene network, establishing a solid foundation for future work during independence. Additionally, career development will continue throughout the mentored phase. The NIH provides workshops on mentorship, leadership, grant writing, research ethics and networking activities which will be completed in parallel with the stated research goals. An advisory committee has also been established to review research progress, provide constructive feedback on experiments and guidance on career objectives. Collectively, this training plan in both research and career development will provide the most comprehensive analysis of MCPH to date and unlock the molecular underpinnings of the disorder while ensuring success in all phases as an independent investigator.
Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by reduced brain size and life span resulting from mutations in MCPH genes. While the clinical aspects of the disorder are well characterized, the underlying molecular mechanisms remain poorly understood, limiting our ability to fully understand how genetic & cellular defects contribute to altered tissue function in MCPH patients. This proposal seeks to uncover the mechanisms by which MCPH genes promote proper brain size, leading to a better understanding of brain development, growth and evolution.