Structural Brain Disorders

A central question in developmental neuroscience is the elucidation of the genetic programs that govern mammalian brain morphogenesis. Determining the cellular and molecular basis of rare congenital brain disorders, including those that disrupt the structure of the neocortex, promises not only to inform our understanding of disease pathogenesis, but also to provide mechanistic insight into human cortical development.

We use a combination of mouse models, patient-derived induced pluripotent stem (iPS) cells and iPS cell-derived neuroepithelial stem cells, cortical neurons and cerebral organoids and employ cellular, molecular, biochemical, and omics approaches to understand the biology and function of genes associated with primary microcephaly and lissencephaly spectrum disorders.

Our work has centered on WDR62, a frequent cause of microcephaly and severe brain malformations. We established differential action of WDR62 in early and late neural progenitors in mouse models and demonstrated that patient-associated mutations interfere with the shuttling of WDR62 from the Golgi apparatus to the mitotic spindle poles, unveiling a novel mechanism underlying primary microcephaly.

More recently, the identification of rare mutations causing lissencephaly led to cellular and molecular analyses of human cerebral organoids generated from patient-derived iPSCs, revealing hypoactivation of the mTOR pathway as a converging mechanism in lissencephaly spectrum disorders. The translational potential of this ongoing work lies in the demonstration that a brain-specific activator of mTOR prevents and reverses cellular and molecular defects in the lissencephaly organoids.