Rbm8aHaploinsufficiency Disrupts Embryonic Cortical Development Resulting in Microcephaly

Abstract

The cerebral cortex is built during embryonic neurogenesis, a period when excitatory neurons are generated from progenitors. 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 severe microcephaly and defective neurogenesis in the mouse. 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 determine whether reciprocal dosage change of Rbm8a 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 overexpression does not significantly perturb progenitor number or head size. Our findings demonstrate that Rbm8a is an essential neurogenesis regulator, and add to a growing literature highlighting roles for EJC components in cortical development and neurodevelopmental pathology. Our results indicate that disruption of RBM8A may contribute to neurodevelopmental phenotypes associated with proximal 1q21.1 microdeletions.

The exon junction complex in neural development and neurodevelopmental disease

“…Additionally, nearly half of the patients reported in one study had brain size abnormalities, including macrocephaly and microcephaly (Rosenfeld et al, 2012). These clinical observations are consistent with studies of the Rbm8a mouse model, suggesting that microcephaly associated with 1q21.1 deletions may be due to neurogenesis aberrations and influenced by RBM8A loss (Mao et al, 2015). Further evidence implicating RBM8A as a disease gene came from studies of the disorder thrombocytopenia with absent radius syndrome (TAR syndrome).…”

“…The protein partner of MAGOH is RBM8A, which is also highly enriched in neural progenitors (Mao et al, 2015). To formally test its requirement for cortical development, our group generated a conditional floxed Rbm8a allele (Mao et al, 2015). Rbm8a conditional haploinsufficiency, induced with a NSC‐specific Emx1‐ Cre, resulted in severe microcephaly.…”

Interstitial 1q21.1 Microdeletion Is Associated with Severe Skeletal Anomalies, Dysmorphic Face and Moderate Intellectual Disability

“…Therefore, the observation of the HYDIN paralog expressed in humans may be a candidate gene for microcephaly, since it is only expressed in the brain and is important in head size determination [Brunetti-Pierri et al, 2008;Olbrich et al, 2012]. Recently, it was shown that the RBM8A gene within the 1q21.1 region, besides its role in the thrombocytopenia-absent radius syndrome genesis, also disrupts the embryonic cortical development resulting in neurodevelopmental phenotypes associated to microcephaly [Mao et al, 2015;Zou et al, 2015].…”

Prolonged Mitosis of Neural Progenitors Alters Cell Fate in the Developing Brain

“…Interestingly, RGCs are not depleted at the population level in microcephalic Magoh +/− cortical columns (Silver et al, 2010), suggesting Magoh regulation of RGCs is especially relevant in the tangential dimension. Magoh is part of the exon junction RNA binding complex, components of which are associated with human neurodevelopmental phenotypes including microcephaly (Mao et al, 2015; Pilaz and Silver, 2015). Our findings may have broad relevance for understanding roles of this complex in human brain development.…”