Gene regulatory networks controling the nematode molt
L3 stage B. malayi
Molting involves the replacement of an animal’s exoskeleton to allow further growth and is an essential developmental process in Ecdysozoans, such as arthropods and nematodes. My long-term goal is to define molting GRNs in C. elegans and the filarial nematode B. malayi, a human pathogen and the causative agent of lymphatic filiarisis. By comparing the C. elegans molt network to that of B. malayi, we will test the hypothesis that transcription factor regulation of core elements of the molting network are conserved between free-living and parasitic nematodes. These two nematodes diverged 300-500 million years ago; despite conservation of only half of their genes, all known C. elegans molting genes are conserved in Brugia, including two nuclear hormone receptor transcription factors (NHR-23 and NHR-25) essential for C. elegans molting. By studying a single GRN in these two nematodes, we gain insight into evolution of GRNs. The molting GRN regulates processes throughout the entire animal, thus in the long-term this work will examine how the GRN integrates cell-specific, tissue-specific and external cues. Furthermore, defining the NHR-23 and NHR-25 GRNs will inform our understanding of the human homologs of these receptors, and their roles in gene regulation and development.
Understanding the molting GRN also has significant biomedical implications. B. malayi and its close relatives infect over 120 million people worldwide and parasitic nematodes in general afflict an estimated 2.9 billion people worldwide, comprising approximately 85% of global neglected tropical diseases. These insidious parasites depress human health, cognition, and productivity. They increase the severity of diseases caused by viruses and bacterial pathogens, including HIV, malaria, and tuberculosis. Only four drugs exist for treatment of parasitic nematode infection, and the widespread emergence of resistance to these drugs highlights the need for novel therapeutic interventions. In the long-term, we will identify molting-related pharmacological intervention points in parasitic nematode infections, a significant class of neglected tropical diseases.
Understanding the molting GRN also has significant biomedical implications. B. malayi and its close relatives infect over 120 million people worldwide and parasitic nematodes in general afflict an estimated 2.9 billion people worldwide, comprising approximately 85% of global neglected tropical diseases. These insidious parasites depress human health, cognition, and productivity. They increase the severity of diseases caused by viruses and bacterial pathogens, including HIV, malaria, and tuberculosis. Only four drugs exist for treatment of parasitic nematode infection, and the widespread emergence of resistance to these drugs highlights the need for novel therapeutic interventions. In the long-term, we will identify molting-related pharmacological intervention points in parasitic nematode infections, a significant class of neglected tropical diseases.
Induction of Brugia molting in vitro. L3s cultured as described in the text undergo molting after six days of culture. A) Molting animals can be distinguished by the compaction of their cuticle. B) Unmolted L3s are long, narrow, and highly active. C) Shed cuticle, very faint.
