Mitosis progression, cell fate, and microcephaly
How do RNA binding proteins influence neural progenitors? Using mice haploinsufficient for an RNA binding protein, called Magoh, we discovered a new role for mitosis length in cell fate specification. Please see our recent 2016 study in Neuron: Prolonged mitosis of neural progenitors alters cell fate in the developing brain. We discovered that Magoh haploinsufficient neural progenitors exhibit mitotic delay, and these progenitors directly produce more neurons instead of new progenitors. This fascinating phenotype is recapitulated using pharmacology, revealing that prolonged progenitor mitosis is sufficient to alter neural cell fates and identifying one explanation for microcephaly.
We continue to study the link between prolonged mitosis and altered cell fate using novel in vivo models, live imaging as well as primary cells.
The RNA binding exon junction complex and microcephaly
The exon junction complex (EJC) is an RNA binding complex implicated in many stages of the RNA life cycle, including splicing, translation, decay, and RNA localization. See this recent review from our lab to learn more. We previously discovered that haploinsufficiency for the EJC protein, Magoh, results in microcephaly, due to defects in neural progenitor proliferation and neuronal apoptosis. Please see our 2010 study in Nature Neuroscience and our 2014 study in Genesis. Magoh binds to two other RNA binding protein, Eif4a3 and Rbm8a. RBM8A is located with the 1q21.1 locus in humans, which is associated with microcephaly and autism. We discovered that both Eif4a3 and Rbm8a haploinsufficiency cause microcephaly in mice, and identified common alterations, including p53, downstream of all 3 genes. Please see our 2015 study in The Journal of Neuroscience and our 2016 study in PLoS Genetics! Listen to Debby discuss the PLoS Genetics study on Microcephaly on the Radio! Interestingly, genetic analyses also told us that a 3rd binding partner, Casc3, does not influence brain development in the same way, as reported in 2016 in RNA.
We continue to use mouse and human models to understand how the EJC controls brain development and disease.
RNA binding proteins in intellectual disability. How do de novo mutations in RNA binding proteins disrupt neurodevelopment? We are very interested in linking our studies of development to understand the etiology of neurodevelopmental diseases. We are especially interested in how an RNA binding protein called DDX3X influences brain development. De novo mutations in DDX3X underlie 1-3% of female intellectual disabilities and are linked to brain malformations including callosal agenesis. We are collaborating with Dr. Elliott Sherr, a human geneticist at UCSF, to understand how DDX3X missense and nonsense mutations affect cortical development and RNA metabolism. Please see our recent study in Biorxiv!
Zika and mechanisms of microcephaly. We are studying how ZIKA virus infection prenatally leads to microcephaly by influencing neural progenitors. This work is in collaboration with Dr. Stacy Horner, a flavirologist also at Duke.