A fundamental question in developmental neurobiology is the idea of brain growth control. In other words, how does a brain know how big it should be? And what are the genetic requirements for ensuring that this pathway is executed faithfully during development? We approach this question by studying genes that we know are important for this process based on their ability to disrupt proper brain growth when mutated. Mutations in this class of genes give rise to a very distinct small brain phenotype, which is clinically defined as microcephaly.
Microcephaly is a neurological disorder characterized by a reduction in brain volume, intellectual disabilities and reduced life span. While the clinical features are well defined, our understanding of the molecular mechanisms responsible are not. Mutations in a number of genes have been found in human microcephaly patients. These genes play a role in different cellular pathways, including centriole biogenesis, cell division, DNA replication and repair, the cytoskeleton, and signalling. However, many open questions remain. For example, do these genes have additional cellular functions that are ultimately responsible for the microcephaly phenotype? How are these inputs coordinated as part of a larger 'microcephaly gene network' to ensure proper brain growth?
We are actively pursuing these questions to provide a comprehensive molecular understanding of how brain growth control is achieved. Currently, we are investigating the molecular mechanism by which abnormal spindle, the most commonly mutated gene in human microcephaly patients, promotes brain size using a combination of genetics, high resolution imaging and -omics approaches. In addition, we are examining these brains at 'cell-level' resolution to identify the entire spectrum of cell biological defects responsible for this disorder. Finally, we are also probing genetic interactions to identify how the 'microcephaly gene network' has been hardwired throughout evolution to instruct brain growth control.
Microcephaly is a neurological disorder characterized by a reduction in brain volume, intellectual disabilities and reduced life span. While the clinical features are well defined, our understanding of the molecular mechanisms responsible are not. Mutations in a number of genes have been found in human microcephaly patients. These genes play a role in different cellular pathways, including centriole biogenesis, cell division, DNA replication and repair, the cytoskeleton, and signalling. However, many open questions remain. For example, do these genes have additional cellular functions that are ultimately responsible for the microcephaly phenotype? How are these inputs coordinated as part of a larger 'microcephaly gene network' to ensure proper brain growth?
We are actively pursuing these questions to provide a comprehensive molecular understanding of how brain growth control is achieved. Currently, we are investigating the molecular mechanism by which abnormal spindle, the most commonly mutated gene in human microcephaly patients, promotes brain size using a combination of genetics, high resolution imaging and -omics approaches. In addition, we are examining these brains at 'cell-level' resolution to identify the entire spectrum of cell biological defects responsible for this disorder. Finally, we are also probing genetic interactions to identify how the 'microcephaly gene network' has been hardwired throughout evolution to instruct brain growth control.
Live cell imaging of central brain neuroblasts from wildtype and asp mutant third instar larva expressing B-tubulin::GFP. Note mitotic spindle defects and delayed mitotic exit in asp mutants.
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3D u-CT imaging of an adult wildtype, asp mutant and transgenic rescue fly expressing a small piece of Asp's N-terminus (AspMF::GFP). The visual system of the brain is highlighted (medulla, green; lobula, blue; lobula plate, yellow).
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