The function of chromatin remodeling in the patterning of the salamander limb

University Of Massachusetts Boston, Dorchester MA

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Abstract

PROJECT SUMMARY Injured mammalian limb cells are limited in their ability to respond to regenerative signals, and the goal of this project is to contribute to identifying roadblocks to regenerative competency by studying how this property is naturally induced in axolotl limb cells. Working toward this goal, this research focuses on how axolotl limb cells become competent to respond to signals that organize, or pattern, the missing limb structure. The complexity of the cell populations and signals that are in amputation blastemas has been a key challenge to studying patterning competency in the past, and this research employs a new simplified regenerative paradigm called the CALM that specifically assays this cellular property. Preliminary data using the CALM show that a combination of FGF and BMP signaling is sufficient to induce patterning competency in limb wound cells, the Nrg1/ErBB pathway is a downstream epigenetic regulatory target of these signals during this process, and that cells from different limb locations respond uniquely to both inductive and patterning signals. While it is known that FGF/BMP are crucial in the induction of patterning competency, several unknowns prevent our mechanistic understanding of this including: 1) what are the pathways downstream of FGF/BMP that are fundamental in this process, and 2) how does A and P positional information mediate different responses to BMP/FGF signals, in particular gene expression regulation. To address these gaps, our approach objectives are: (Aim 1) to test the requirement and sufficiency of Nrg1/ErBB signaling in the induction of patterning competency and identify the downstream gene targets and (Aim 2) to identify the pathways activated by FGF and BMP ligands that are required for the induction of patterning competency and the effect of positional information on the downstream gene regulations. The data collected will resolve the upstream pathways that regulate competency, and how positional context influences the cellular responses to inductive signals. In addition to enhancing our understanding of the molecular underpinnings of regenerative competency in limb cells, the proposed research has been specifically designed for the inclusion of undergraduate researchers to provide students with hands-on research experiences.