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、哺乳和摄食。这些激素中的许多在下丘脑的室旁核和视上核（PVN和SON）中产生。在小鼠中，Sim1和Sim2是2个转录因子，指导这些产生突触的PVN和SON神经元的终末分化。特别重要的是，在小鼠模型和人类中，Sim1杂合性和Sim2过表达分别直接涉及肥胖和精神发育迟滞的发病机制。在上一个资助期，我们发现1）在Sim1突变小鼠中，在正常解剖位置未发现表达PVN和SON的神经元，2）Sim1杂合子小鼠出现极度肥胖。在这里，我们提出了以下目标来研究这两个悬而未决的问题：目的1）表征Sim1突变体的神经元迁移和轴突投射缺陷。目的2）研究下丘脑室旁核和视上核神经元迁移和轴突投射的分子机制。我们的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）基因与普拉德-威利综合征（PWS）的发生有关，而SIM1基因与一种类似于PWS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。我们的目标是在Sim1和Ndn之间建立调节关系。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.