otpbfunctions in a Lef1-dependent transcriptional network required for expression of the stress response inhibitorcrhbpin the zebrafish hypothalamus

Abstract

AbstractThe vertebrate hypothalamus regulates physiological and behavioral responses to environmental stimuli through the function of evolutionarily-conserved neuronal subpopulations. Our previous work found that mutation of zebrafishlef1, which encodes a transcriptional mediator of the Wnt signaling pathway, leads to the loss of hypothalamic neurons and behavioral phenotypes that are both associated with stress-related human mood disorders However, the specific Lef1 target genes that link neurogenesis to behavior remain unknown. One candidate isotpb, which encodes a transcription factor with known roles in hypothalamic development. Here we show thatotpbexpression in the posterior hypothalamus is Lef1-dependent, and that likelef1, its function is required for the generation ofcrhbp+ neurons in this region. Transgenic reporter analysis of acrhbpconserved noncoding element suggests thatotpbparticipates in a transcriptional regulatory network with other Lef1 targets. Finally, consistent with a role forcrhbpin inhibiting the stress response, zebrafishotpbmutants exhibit decreased exploration in a novel tank diving assay. Together our findings suggest a potential evolutionarily-conserved mechanism for the regulation of innate stress response behaviors through Lef1-mediated hypothalamic neurogenesis.