Project Summary and Abstract
The long-term goal of my research group is to understand the mechanisms through which nematodes
molt and to use this information to understand fundamental, conserved biological processes. We will determine
how the collagenous extracellular matrix (ECM) that surrounds all cells is precisely remodeled during
development, informing mammalian dermal physiology, wound healing, and tumor invasion through the ECM.
We will reveal how animals coordinate precise patterns of oscillatory gene expression during development. We
will explore whether nematode molting is hormonally-regulated, a long-standing question in the field. This work
will also provide fundamental insight into how animals couple development with diet. We are also interested in
nematode-specific biology, as it offers an intervention point to combat parasitic nematode infections. As a group,
these animals afflict an estimated 1.5 billion people worldwide, comprising approximately 85% of global
neglected tropical diseases. They also threaten food security by infecting crops and livestock. Our long-term
goal is to define the mechanisms that ensure faithful molting at the molecular, cellular, and organismal level in
C. elegans and then extend our work into parasitic nematode models.
Molting involves the coordinated replacement of an animal’s exoskeleton to allow further growth and
requires intracellular trafficking, extracellular matrix remodeling, assembly of the new exoskeleton, and a
stereotyped series of behaviors to escape the old exoskeleton. In contrast to the deep understanding that we
have gained on the mechanisms of arthropod molting, we are only beginning to understand the functions of
genes that regulate nematode molting. Shedding light on nematode molting promises to reveal how molting gene
regulatory networks have evolved, and to provide pharmacological intervention points in parasitic nematodes.
The C. elegans molt cycle is an oscillatory process with similarities to mammalian circadian rhythms, and
is regulated by homologs of mammalian clock proteins, such as NHR-23 (homolog of mammalian RORa). The
C. elegans molt can lengthen or shorten depending on dietary input, making it a valuable model to explore how
environment and diet can impact developmental timing. We will use NHR-23 as an entry point to define upstream
regulatory signals and coordinated action of downstream effectors. Our working hypothesis is that steroid
hormone signaling controls NHR-23 to promote the oscillatory gene expression that initiates molting and
coordinates ECM remodeling. Our aims test key aspects of this hypothesis. In Aim 1, we determine how ECM
remodeling during molting is coordinated by the concerted action of proteases and protease inhibitors. In Aim 2,
we will determine how oscillatory gene expression is promoted during molting. In Aim 3, we will test whether a
ligand drives nematode molting, an elusive question in the field.