Function of Mammalian Single-minded Genes SIM1 and SIM2

描述（由申请人提供）：神经内分泌激素调节多种生理过程，包括排尿、哺乳和食物摄入。这些激素中的许多是在下丘脑的室旁核和视上核（PVN和SON）中产生的。在小鼠中，Sim1和Sim2是2个转录因子，指导这些产生激素的PVN和SON神经元的终端分化。特别重要的是，在小鼠模型和人类中，Sim1杂合性和Sim2过表达分别与肥胖和智力低下的发病机制直接相关。在之前的资助期内，我们发现1)在Sim1突变小鼠中，没有发现表达激素的PVN和SON神经元处于正常解剖位置；2)Sim1杂合小鼠出现极度肥胖。在此，我们提出以下目标来研究这两个突出问题：目标1)表征Sim1突变体的神经元迁移和轴突投影缺陷。目的是了解下丘脑的结构组织和PVN和SON的神经元回路；目的2)研究PVN和SON神经元迁移和轴突投射的分子机制。目标是确定控制这两个过程的分子。目的3)确定Necdin是否是Sim1和/或Sim2的下游基因。NECDIN （NDN）基因与PWS有关，而SIM1基因与PWS类似的单倍体不足疾病有关，称为PWS样（PWSL）。PWS和PWSL的共同病理是肥胖。我们的目标是建立Sim1和Ndn之间的监管关系。我们希望通过提出的研究，揭示由Sim1和Sim2控制的分子程序，从而了解其基因剂量改变引起的人类疾病。

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.