Identification of genetic pathways that regulate kidney cell fate: Hand2 inhibits intermediate mesoderm development

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PROJECT SUMMARY The Principal Investigator seeks mentored training to investigate the genetic regulation of early kidney development using the zebrafish embryo. Research and training will be carried out in the laboratory of Dr. Deborah Yelon, with the support of the Division of Pediatric Nephrology at the University of California, San Diego and an advisory committee composed of specialists in kidney development and disease and in the genetic regulation of organ formation. The objective is to obtain training and pursue laboratory research that will lead to the Principal Investigator's development into an independent physician-scientist. The overall goal of the research is to elucidate the genetic pathways regulating early stages of kidney development in order to gain insight into the etiology of kidney birth defects and to instruct strategies in regenerative medicine. To do so, the PI will take advantage of the genetic and embryological benefits of using the zebrafish as a model organism. Like mammalian kidneys, zebrafish kidneys are derived from the intermediate mesoderm (IM). Work in multiple organisms, including zebrafish, has defined several conserved factors that promote IM formation. However, the mechanisms defining the boundaries that distinguish the IM from its neighboring territories are not yet understood. Recent studies by the PI suggest that the bHLH transcription factor Hand2 defines the lateral border of the IM by regulating cell fate decisions within the posterior mesoderm. While the IM and embryonic kidney are expanded in hand2 mutants, hand2 overexpression results in strong inhibition of IM and kidney development. Additionally, hand2 is expressed in a portion of the posterior mesoderm that lies laterally adjacent to the IM. Venous progenitors arise between these two territories, and hand2 promotes venous progenitor development while inhibiting IM formation at this interface. The lateral hand2-expressing territory also expresses osr1, a zinc-finger transcription factor previously implicated in promoting kidney formation, and genetic analyses suggest that hand2 and osr1 have functionally antagonistic roles during kidney development. Together, these data shed light on a previously unrecognized genetic network that regulates IM boundaries, suggesting a model in which hand2 functions in opposition to osr1 to control the allocation of progenitor cells to kidney and vein lineages. To test this model, two specific aims will be pursued. The first aim will define the role of hand2 in the inhibition of IM lineage specification, using high-resolution fate map analysis and cell autonomy studies. The second aim will identify genes in the pathways through which hand2 and osr1 control IM specification, using complementary candidate gene and whole transcriptome approaches to identify relevant partner and effector genes. These studies will elucidate the role of hand2 in IM formation and illuminate the pathways that define the boundaries of the IM by balancing formation of the kidney and vein lineages. Over the long term, detailed comprehension of these genetic pathways should improve diagnostic, prognostic, and therapeutic options for patients with kidney disease.