Neurobiology of Disease Rbm8aHaploinsufficiency Disrupts Embryonic Cortical Development Resulting in Microcephaly

The cerebral cortex is built during embryonic neurogenesis, a periodwhen excitatory neurons are generated fromprogenitors. Defects in neurogenesis can cause acute neurodevelopmental disorders, such as microcephaly (reduced brain size). Altered dosage of the 1q21.1 locus has been implicated in the etiology of neurodevelopmental phenotypes; however, the role of 1q21.1 genes in neurogenesis has remained elusive. Here, we show that haploinsufficiency for Rbm8a, an exon junction complex (EJC) component within 1q21.1, causes severemicrocephaly anddefective neurogenesis in themouse. At the onset of neurogenesis,Rbm8a regulates radial glia proliferation and prevents premature neuronal differentiation. Reduced Rbm8a levels result in subsequent apoptosis of neurons, and to a lesser extent, radial glia. Hence, compared to control, Rbm8a-haploinsufficient brains have fewer progenitors and neurons, resulting in defective cortical lamination. To determinewhether reciprocal dosage change ofRbm8a alters embryonic neurogenesis, we overexpressed human RBM8A in two animal models. Using in utero electroporation of mouse neocortices as well as zebrafish models, we find RBM8A overex-pression does not significantly perturb progenitor number or head size. Our findings demonstrate thatRbm8a is an essential neurogen-esis regulator, and add to a growing literature highlighting roles for EJC components in cortical development and neurodevelopmental pathology. Our results indicate that disruption of RBM8Amay contribute to neurodevelopmental phenotypes associated with proximal 1q21.1 microdeletions. Key words: cortical development; embryonic; microcephaly; neurogenesis; radial glia; rbm8