Professor, Department of Biology
Ph.D. Brandeis University
B.S. Utah State
Research Interests: Specification and patterning of the vertebrate nervous system with a focus on developmental interactions between the nervous system, immune system, and host-associated microbiota
Overview: The vertebrate nervous system is composed of a large number of neurons with diverse characteristics that ultimately form the circuits that underlie an animal’s behavioral repertoire. We are interested in several aspects of this process including: 1) How neuronal diversity is generated during development: how are the correct number of cells specified for specific neural and glia fates at particular times and in particular locations? 2) How neuronal circuits are wired up: how do neurons make appropriate connections with their synaptic partners. 3) What are the roles of host-associated microbiota and the immune system during neural development: how do microbes associated with the host interact with the immune system and with the nervous system to shape neuronal architecture, circuitry, and function? We use an approach that combines cellular, molecular, genetic, and microbiological manipulations with live imaging in zebrafish to investigate these questions with the goal of understanding the mechanisms underlying neural development.
Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development.
Dev Biol. 2019 Aug 05;:
Authors: Ganz J, Melancon E, Wilson C, Amores A, Batzel P, Strader M, Braasch I, Diba P, Kuhlman JA, Postlethwait JH, Eisen JS
Intestinal tract development is a coordinated process involving signaling among the progenitors and developing cells from all three germ layers. Development of endoderm-derived intestinal epithelium has been shown to depend on epigenetic modifications, but whether that is also the case for intestinal tract cell types from other germ layers remains unclear. We found that functional loss of a DNA methylation machinery component, ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1), leads to reduced numbers of ectoderm-derived enteric neurons and severe disruption of mesoderm-derived intestinal smooth muscle. Genetic chimeras revealed that Uhrf1 functions both cell-autonomously in enteric neuron precursors and cell-non-autonomously in surrounding intestinal cells, consistent with what is known about signaling interactions between these cell types that promote one another's development. Uhrf1 recruits the DNA methyltransferase Dnmt1 to unmethylated DNA during replication. Dnmt1 is also expressed in enteric neurons and smooth muscle progenitors. dnmt1 mutants have fewer enteric neurons and disrupted intestinal smooth muscle compared to wildtypes. Because dnmt1;uhrf1 double mutants have a similar phenotype to dnmt1 and uhrf1 single mutants, Dnmt1 and Uhrf1 must function together during enteric neuron and intestinal muscle development. This work shows that genes controlling epigenetic modifications are important to coordinate intestinal tract development, provides the first demonstration that these genes influence development of the ENS, and advances uhrf1 and dnmt1 as potential new Hirschsprung disease candidates.
PMID: 31394080 [PubMed - as supplied by publisher]