Function of Mammalian Single-minded Genes SIM1 and SIM2

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DESCRIPTION (provided by applicant): Neuroendocrine hormones regulate diverse physiological processes, including urination, lactation, and food intake. Many of these hormones are produced in the paraventricular and supraoptic nuclei (PVN and SON) of the hypothalamus. In the mouse, Sim1 and Sim2 are 2 transcription factors that direct the terminal differentiation of these hormone-producing PVN and SON neurons. Of particular importance, in mouse models and humans, Sim1 heterozygosity and Sim2 over-expression have been directly implicated in the pathogenesis of obesity and mental retardation, respectively. In the previous funding period, we found that 1) in Sim1 mutant mouse, hormone-expressing PVN and SON neurons are not found in their normal anatomical positions, and that 2) Sim1 heterozygous mice develop extreme obesity. Here, we propose the following aims to study these 2 outstanding issues: Aim 1) Characterization of the neuronal migration and axonal projection defects of Sim1 mutants. The goal is to understand the structural organization of the hypothalamus and the neuronal circuitry of the PVN and SON; Aim 2) Investigation of the molecular mechanisms underlying PVN and SON neuronal migration and axonal projection. The goal is to identify the molecules that control these 2 processes. Aim 3) Determine if Necdin is a downstream gene of Sim1 and/or Sim2. The NECDIN (NDN) gene is implicated in causing the Prader-Willi-Syndrome (PWS), whereas the SIM1 gene is associated with a haploid-insufficient disorder similar to PWS, named PWS-Like (PWSL). The common pathology of PWS and PWSL is obesity. Our goal is to establish a regulatory relationship between Sim1 and Ndn. Through the proposed research, we hope to unravel the molecular programs controlled by Sim1 and Sim2, thereby understanding the human diseases caused by the alteration of their gene dosage.