An intimate link between centrosome function and neurogenesis is revealed by the identification of many genes with centrosome-associated functions that are mutated in microcephaly disorders. Consistent with the major role of the centrosome in mitosis, mutations in these centrosome-related microcephaly (CRM) genes are thought to affect neurogenesis by depleting the pool of neural progenitor cells, primarily through apoptosis as a consequence of mitotic failure or premature differentiation as a consequence of cell cycle delay and randomization of spindle orientation. However, as suggested by the wide range of microcephaly phenotypes and the multifunctional nature of many CRM proteins, this picture of CRM gene function is incomplete. Here, we explore several examples of CRM genes pointing to additional functions that contribute to microcephaly, including regulation of cell cycle signaling, actin cytoskeleton, and Hippo pathway proteins, as well as functions in postmitotic neurons and glia. As these examples are likely just the tip of the iceberg, further exploration of the roles of microcephaly-related genes are certain to reveal additional unforeseen functions important for neurodevelopment.

Septins are cytoskeletal proteins that form hetero-oligomeric complexes and function in many biological processes, including cytokinesis. Drosophila melanogaster has five septin genes. Sep5, which is the most recently evolved septin gene in Drosophila, is a retrogene copy of Sep2. Sep5 mutants appear wild type, whereas Sep2 mutant females are semisterile. Their ovaries have egg chambers containing abnormal numbers of nurse cells. The egg chamber phenotype is rescued to wild type by expressing a Sep2 cDNA, but it is only partially rescued by expressing a Sep5 cDNA, showing that these paralogs have diverged in function at the protein level. Sep2 Sep5 double mutants have an early pupal lethal phenotype and lack imaginal discs, suggesting that these genes have redundant functions during imaginal cell proliferation.

The septin family of hetero-oligomeric complex-forming proteins can be divided into subgroups, and subgroup members are interchangeable at specific positions in the septin complex. Drosophila melanogaster has five septin genes, including the two SEPT6 subgroup members Sep2 and Sep5. We previously found that Sep2 has a unique function in oogenesis, which is not performed by Sep5. Here, we find that Sep2 is uniquely required for follicle cell encapsulation of female germline cysts, and that Sep2 and Sep5 are redundant for follicle cell proliferation. The five D. melanogaster septins localize similarly in oogenesis, including as rings flanking the germline ring canals. Pnut fails to localize in Sep5; Sep2 double mutant follicle cells, indicating that septin complexes fail to form in the absence of both Sep2 and Sep5. We also find that mutations in septins enhance the mutant phenotype of bazooka, a key component in the establishment of cell polarity, suggesting a link between septin function and cell polarity. Overall, this work suggests that Sep5 has undergone partial loss of ancestral protein function, and demonstrates redundant and unique functions of septins.

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