Isoform-Specific LEF1 Function in Hypothalamic Neurogenesis and Behavior

Dysfunction of the Wnt signaling pathway has been associated with mental ilness, but the underlying molecular and cellular mechanisms remain elusive. Our laboratory has discovered an evolutionarily conserved role for the Wnt transcriptional effector Lef1 in generating hypothalamic neurons and innate behaviors linked to stress. LEF1 variants could thus contribute to human stress-related mood disorders, and we propose that the distinct expression and function of two highly conserved protein isoforms could provide a way to separate this role from the other essential roles of Lef1 in development. We will use zebrafish to test the hypothesis that isoform- specific control of Lef1-dependent transcription regulates hypothalamic neurogenesis and stress- related behavior. In Aim 1 we will determine how the Lef1 N-tail and B-tail isoforms affect protein function, and in Aim 2 we will determine whether each isoform is specifically required for neurogenesis and behavior. Our goal is to establish an evolutionarily conserved model that we can eventually translate to human mental health. Project Number: 1R21MH138856-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: RICHARD DORSKY | Institution: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH, SALT LAKE CITY, UT | Award Amount: $423,500 | Activity Code: R21 | Study Section: Neurogenesis and Cell Fate Study Section[NCF] View on NIH RePORTER: https://reporter.nih.gov/project-details/11233558