Human Brain Evolution Driven by Drp1 Hiromi Sesaki and Kie Itoh Department of Cell Biology, Johns Hopkins University School of Medicine
Dynamin-related protein 1 (Drp1) is a mechano-chemical GTPase that mediates mitochondrial division. Drp1 is highly conserved from yeast to humans. While yeast express only one isoform, humans express several isoforms via the splicing of alternative exons. However, it is unknown whether the generation of these Drp1 isoforms is involved in evolution. To address this question, we performed comparative analyses of the gene structure of Drp1 and its isoform profile in humans and mice. We found that humans have lost an alternative exon located in the GTPase domain. To determine the function of this exon (“exon A”), we humanized the Drp1 gene in mice using the CRISPR/Cas9 genome editing system. Humanized Drp1 mice exhibited an increased number of primary dendrites in neurons and their brain wiring. These mice also exhibited enhanced sensorimotor gating, the ability to filter out unnecessary information, in prepulse inhibition tests. Because exon A creates several different isoforms in combination with other exons, we tested which Drp1 protein isoform was critical to the changes in the neuronal structure. By knocking down individual isoforms during brain development in vivo using in utero electroporation, we found that the specific loss of a previously uncharacterized isoform phenocopies humanized Drp1 mice. This isoform is highly enriched in the brain. In addition, by knocking down this isoform in mature neurons in vitro, we showed that the loss of isoform creates ectopic dendrites in a manner dependent on neural communication via action potentials. These data suggest a mechanism by which Drp1 remodels neuronal structure during development and even after its completion. We propose that the brain-enriched isoform of Drp1 drives the structural and functional evolution of the brain. In this presentation, we will discuss the function of this novel brain isoform of Drp1.
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