Andrew Chisholm

Research

How the skin and nervous system maintain and repair themselves

The skin (epidermis) and the nervous system are each capable of regenerative responses to injury. Epidermal epithelia undergo robust wound healing responses in response to physical injury, related to the skin’s ability to maintain its long-term integrity. Neurons can also respond rapidly to damage and undergo regenerative regrowth leading to restoration of connectivity and function.

We study these processes in the nematode worm Caenorhabditis elegans, a tractable model for many aspects of skin and nervous system development and function. The C. elegans skin is a simple epithelium that encloses the entire animal during embryonic development and subsequently grows in size and complexity. The skin generates the cuticle, an apical extracellular matrix that mediates many skin functions and which serves as the animal’s exoskeleton. The nervous system contains only 302 neurons with simple stereotyped morphology. Neurons are closely associated with the epidermis, which has functions analogous to those of glial support cells.

Skin wound healing

The epidermis forms the first line of defense against environmental challenges including many microbial pathogens. In collaboration with Nathalie Pujol and Jonathan Ewbank (Marseille) we developed the C. elegans model for epidermal wound responses and repair and identified Death Associated Protein Kinase (DAPK) as a coordinate regulator of damage responses. We further discovered that DAPK acts via the epidermal microtubule cytoskeleton (Chuang et al., 2016, eLife). We have elucidated how the epidermis detects wounds, focusing on immediate damage response signals such as calcium, mitochondrial morphology, and reactive oxygen species (Xu and Chisholm, 2014, Dev. Cell). Current projects are exploring how the skin’s apical extracellular matrix (cuticle) responds to injury and repairs itself (see review by Zheng et al 2020, Faculty Reviews).

A ring of actin bundles forms after wounding (Suhong Xu)

Axon regeneration

The ability of axons to regrow after injury has been known for over a century and has been studied in a wide range of animals. However the molecular mechanisms of axon regeneration remain poorly understood owing in part to the lack of genetically tractable models. In collaboration with Yishi Jin (UCSD) we showed that C. elegans axons are capable of robust axon regeneration (Wu et al., 2007, PNAS). C. elegans axon regeneration requires the DLK-1 MAP kinase pathway, second messenger cascades, and axonal microtubule dynamics. We exploited the tractable genetics of C. elegans to test over 1500 genes for roles in axon regrowth and identified many genes with previously unknown roles as positive or negative regulators of regrowth (Chen et al., 2011, Neuron). The function of axon regeneration in the natural environment of C. elegans is not yet clear but may be related to the capacity of neurons to maintain their shape over the life of the animal. Current projects focus on factors such as DIP-2 (Noblett et al., 2019, J Cell Biol.) or CAR-1 (Tang et al 2020, Curr. Biol.) that regulate the shape of mature neurons.

Axon regeneration after laser injury (Lizhen Chen)