Investigation into the roles of a novel vertebrate gene, S52, in CNS development and pathogenesis

发育调控基因发生突变或缺失可导致多种疾病，包括人类神经系统疾病。因此，了解发育的基本分子遗传学是很重要的。我们发现了一种新的人类基因，称为S52，并在老鼠身上发现了与之相当的基因。从这些基因中获得的预测蛋白表明，S52蛋白可能与体内其他蛋白（可能是神经生长因子）相互作用，调节正常发育，并可能促进胚胎神经细胞的存活。引人注目的是，秀丽隐杆线虫，一种进化非常遥远的动物，也有一个与人类非常相似的基因。这种蛋白质在整个进化过程中一直如此保守，这一事实支持了S52功能在发育中很重要的观点。S52 mRNA在发育中的大脑中表达，尤其是在一组叫做底板的特殊细胞中。底板是一种在发育中的大脑中具有组织细胞模式和分化能力的组织。S52也在发育早期的运动神经元中表达，后来在脊髓背神经元的一个亚群中表达。我们已经将S52定位到人类2号染色体的短臂上（2p15-22）。2号染色体的这一区域与几种具有神经缺陷的人类遗传疾病有关。根据我们的初步数据，我们认为S52不仅对正常的大脑发育很重要，而且可能在一种称为痉挛性截瘫4型（SPG4）的人类神经系统疾病中发生突变，这种疾病的特征是脊髓神经细胞的退化。该项目的目的是进一步了解该基因的功能并研究其在疾病中的作用。这些知识将有助于全面提高我们对人类大脑发育和神经系统疾病的分子基础的理解。

Developmentally regulated genes when mutated or deleted can cause a variety of diseases including neurological diseases in humans. It is therefore important to understand the fundamental molecular genetics of development. We have discovered a novel human gene, termed S52, and its equivalent gene in the mouse. The predicted protein derived from these genes would indicate that S52 protein may interact with other proteins, possibly nerve growth factors, in the body to regulate normal development and possibly facilitate the survival of nerve cells in embryos. Strikingly, the worm C. elegans, an evoluationary very distant animal, also has a very similar gene to human. The fact that the protein has been so conserved throughout evolution supports the idea that S52 function is important in development. S52 mRNA is expressed in the developing brain, particularly in a special group of cells called the floor plate. Floor plate is a tissue that has ability to organize the patterning and differentiation of cells within the developing brain. S52 is also expressed in motor neurons in early stages of development and later in a subset of dorsal spinal cord neurons. We have mapped S52 to the short arm of human chromosome 2 (2p15-22). This region of chromosome 2 is linked to several human genetic diseases with neurological defects. Based on our preliminary data, we think S52 is not only important for normal brain development but may be mutated in a human neurological disease called Spastic Paraplegia Type 4 (SPG4) which is characterized by a degeneration of nerve cells in the spinal cord. The aim of this project is to further our understanding of the function of this gene and investigate its role in disease. This knowledge will contribute to an overall increase in our understanding of the molecular basis of brain development and neurological disease in humans.