NR4A REGULATION OF ORGANOGENESIS

Louisiana State Univ A&M Col Baton Rouge, Baton Rouge LA

Investigators

Linked publications & trials

Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of the research in my laboratory is to dissect the cellular activities of NR4A NRs in the genetic model organism C. elegans. The cellular activities of NR4A, including mechanisms of transcriptional regulation and interactions with signal transduction pathways, are poorly understood. We have identified an organogenesis function for the C. elegans NR4A ortholog, NHR-6, in C. elegans. The INBRE funded project in my laboratory has two primary objectives: test the hypothesis that NHR-6 functions as an organ specific regulator of cell cycle progression and cell differentiation;and 2) to identify the cellular mechanisms of NHR-6 activity. Data from this work will provide key insight into the functions of this group of physiologically and developmentally important proteins with emerging human health relevance. This past year we pursued two specific aims. The first was to identify and characterize genes encoding signaling proteins that genetically interact with nhr-6. The second aim was to determine if NHR-6 functions through a DNA-binding mechanism. Progress has been made on both aims. For the first aim, we have determined that nhr-6 genetically interacts with genes that encode components of the Eph receptor tyrosine kinase signaling pathway. Our data suggest that NHR-6 and Eph receptor signaling function together to regulate organ patterning. Future plans are to test the hypothesis that Eph receptor and NHR-6 signaling function in a linear pathway to regulate spermatheca differentiation. For the second aim, we have determined that NHR-6 can activate transcription from the NR4A response element in a mammalian cell line. This activation requires a wild-type DNA-binding domain. We are currently testing the in vivo significance of the NHR-6 DBD using mutant rescue assays and analysis of GFP-tagged NHR-6 reporter transgenes.