SKI PROTO-ONCOGENE AND MOUSE DEVELOPMENT

Ski 原癌基因和小鼠发育

• 批准号: 2403318
• 负责人: CLEMENCIA COLMENARES
• 金额: $ 9.61万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2403318
• 关键词: DNA binding protein; RNase protection assay; cell adhesion; cell differentiation; confocal scanning microscopy; cytogenetics; developmental genetics; developmental neurobiology; embryo /fetus cell /tissue; embryonic stem cell; gene expression; gene mutation; gene targeting; genetically modified animals; immunocytochemistry; laboratory mouse; mammalian embryology; neural plate /tube; neurogenetics; northern blottings; polymerase chain reaction; protooncogene; scanning electron microscopy; southern blotting; transcription factor; western blottings

Genes that encode regulators of gene expression have proved to play a central role in directing mammalian growth and development. The ski proto-oncogene encodes a nuclear protein shown to bind DNA and regulate transcription. Its biological activities impinge on both growth and differentiation pathways in many cell lineages, including the myogenic and hematopoietic systems. To study the physiological functions of ski in vivo, we have disrupted the gene in murine embryonic stem cells, and introduced this mutation into the mouse germ line. Our data shows that ski is essential for normal development and survival, since mice homozygous for the ski mutation die at birth. In addition to generalized growth retardation, the major defect is in the central nervous system. Affected mice are born with exencephaly, a condition that normally results from failure of neural tube closure during neurulation. This result is consistent with studies showing high mRNA expression in the developing neural tube and neural crest. We propose to study the role of ski in neural development by studying the morphogenetic events and molecular mechanisms that are defective in its absence. Our specific aims include: developmental and histological studies of the defective phenotype as well as analyses of expression of other genes such as domain-specific transcription factors and cell adhesion molecules; generation of chimeras using homozygous mutant ES cell lines to study the specific cell types and mechanisms that require ski function; and analysis of homozygous mice expressing a partially defective mutant ski gene. Neural tube defects (NTDs) are some of the most common human congenital abnormalities, and their etiology is almost certainly multifactorial. It has been estimated that 10 or 12 genes control the susceptibility to NTDs, and our studies suggest that ski may be one of this group of genes. The proposed work will test this hypothesis, and should contribute to the understanding the numerous genetic and molecular interactions required for normal neural tube development in mammals.