Function of Mammalian Single-minded Genes SIM1 and SIM2

描述(申请人提供)：神经内分泌激素调节不同的生理过程，包括排尿、哺乳和食物摄入。其中许多激素是在下丘脑室旁核和视上核(室旁核和视上核)产生的。在小鼠中，Sim1和Sim2是两个转录因子，它们指导这些产生激素的PVN和SON神经元的终末分化。尤其重要的是，在小鼠模型和人类模型中，Sim1杂合性和Sim2过度表达分别与肥胖和智力低下的发病机制直接相关。在之前的资助期间，我们发现1)在Sim1突变小鼠中，没有发现激素表达的PVN和SON神经元在其正常的解剖位置，以及2)Sim1杂合子小鼠发生极端肥胖。在这里，我们提出以下两个突出问题的研究：目的1)表征Sim1突变体的神经元迁移和轴突投射缺陷。其目的是了解下丘脑的结构组织以及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Prader-Willi综合征(PWS)有关，而SIM1基因与一种类似PWS的单倍体不足疾病有关，称为PWS样症(PWSL)。PWS和PWSL的共同病理是肥胖。我们的目标是在Sim1和NDN之间建立监管关系。通过这项研究，我们希望解开Sim1和Sim2控制的分子程序，从而了解它们的基因剂量变化引起的人类疾病。

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.