How do our brains develop-from just a few cells in the embryo to a complex adult organ?
We study this fascinating question, focusing on neurogenesis of the cerebral cortex, the process whereby neurons are generated from neural progenitors. Defective neurogenesis impacts the type and number of neurons in the brain, and can cause broad neurodevelopmental disorders such as microcephaly. We have two major research interests in the lab:
- Genetic basis of brain development and evolution
- RNA regulation, cell fate specification and microcephaly
Genetic basis for brain evolution
We use a multidisciplinary approach (including evolutionary genomics, mouse genetics and embryology) to uncover the genetic changes that underlie human-specific brain development and function. Specifically we are focused on noncoding regulatory sequences called enhancers. We have identified several enhancers which have acquired rapid changes along the human lineage, and are active in the developing brain. Using transient transgenic assays in mice and iPSCs, we study the activity differences and functional impact of these enhancers upon brain development and behavior. We collaborate with Dr. Greg Wray, an evolutionary genomicist. A recent study describing the role of one of these loci, HARE5, was published in Current Biology and was featured in multiple news outlets! Please see a recent review in Bioessays to hear more about this exciting topic.
RNA regulation, cell fate and microcephaly
RNA regulation in neural progenitors:
We are interested in how post-transcriptional regulation impacts neurogenesis. We use genetic, genomic, and live imaging approaches to understand how RNAs and RNA binding proteins regulate neurogenesis. We have ongoing collaborations with RNA biologists to study these processes in vivo.
1) RNA transport and local translation in radial glia
Radial glia progenitors are polarized, with a cell body near the ventricle and extending from this a long basal process which forms endfeet at the top of the brain. Signals nearby the endfeet, within a local niche, have been shown to influence progenitors. But how these signals are relayed to control to neurogenesis is poorly understood. The morphology of radial glia inspired us to investigate roles for mRNA localization in these cells. We recently discovered that mRNAs are actively transported within radial glia, to the top of the brain, where they can be locally translated into protein! RNA transport is dependent upon FMRP, an RNA binding protein that is responsible for Fragile X syndrome. We continue to investigate what mRNAs are localized to these distal structures and translated, how these processes are regulated, and how this impacts neurogenesis! Learn more in our 2016 Current Biology study.
2) Exon junction complex in cortical development
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.
We recently used live imaging of embryonic brain slices and primary cells to investigate how Magoh controls brain development. 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 prolong progenitor mitosis is sufficient to alter neural cell fates. Please see our recent 2016 study in Neuron.
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.
1) Mouse models of microcephaly
We are interested in how defective neurogenesis causes neurodevelopmental disease. We collaborate with human geneticists to understand how human microcephaly genes impact neurogenesis. For an example please see our collaborative study in Neuron and our recent study in The Journal of Neuroscience. The genes we study in mice are outstanding candidates for disease mutations in humans with related neurodevelopmental disorders such as microcephaly and autism. In addition we are very interested in the cellular basis for microcephaly phenotypes.
2) Zika and 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.