Links between mitosis progression, cell fate, and microcephaly
Using mice haploinsufficient for an RNA binding protein, called Magoh, we discovered a new role for mitosis length in cell fate specification. 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. Please see our recent 2016 study in Neuron.
Recently, we extended these findings to the study of interneuron development. We discovered that Magoh is essential for interneuron generation and survival linked to prolonged mitosis of interneuron progenitors. Please see our 2020 study in Development. We also established a new in vivo model system using pharmacology to examine causal relationships between prolonged mitosis and altered cell fate. This highlighted new molecular mechanisms by which altered mitosis duration re-directs fate of progeny in vivo. Please see our 2020 study in Developmental Neuroscience.
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
Magoh is a component of the RNA binding exon junction complex (EJC) which controls many stages of the RNA life cycle, including splicing, translation, decay, and RNA localization. See this recent review from our lab and this one to learn more and RNA binding proteins and the EJC. 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 have used new mouse models to show that both Eif4a3 and Rbm8a haploinsufficiency cause microcephaly in mice, and have 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 our 2016 study in RNA.
We continue to use mouse and human models to understand how the EJC controls brain development and disease.
The RNA binding protein DDX3X in intellectual disability and microcephaly
How do de novo mutations in RNA binding proteins disrupt neurodevelopment? We have been studying 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, and Stephen Floor, an RNA biologist at UCSF, to understand how DDX3X missense and nonsense mutations affect cortical development and RNA metabolism. Our lab discovered that depletion of DDX3X impairs neuron number by disrupting progenitors. Further we showed that missense mutations in DDX3X cause abnormal RNA-protein granule formation in progenitors. This work was published in 2020 in Neuron.
We continue to use mouse models, genomics and imaging to understand how DDX3X mutations impair brain development.