The role of the GPI anchor in Cripto signaling and forebrain specification

GPI 锚在 Cripto 信号传导和前脑规范中的作用

• 批准号: 7667732
• 负责人: David Mark McKean
• 金额: $ 2.65万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667732
• 关键词: Accounting; Activin Receptor; Affect; Anabolism; Animal Model; Anterior; Binding; Biochemical; C-terminal; CFC1 gene; Cell Nucleus; Cell membrane; Cell physiology; Cells; Cholesterol; Chromosome Mapping; Chromosomes, Human, Pair 1; Cleaved cell; Complement; Complex; Conditioned Culture Media; Cultured Cells; Defect; Development; Disease; Distal; Embryo; Embryonal Carcinoma Cell; Endoderm; Endoderm Cell; Enzymes; Epiblast; Extracellular Space; Eye; Failure; Family suidae; Figs - dietary; Fishes; Forebrain Development; Future; GPI Membrane Anchors; Gene Targeting; Genes; Genetic; Genetic Transcription; Glycosylphosphatidylinositol-anchor Biosynthesis Pathway; Glycosylphosphatidylinositols; Hand; Head; Heart; Hemoglobinuria; Holoprosencephaly; Human; Knock-out; Knockout Mice; Lead; Life; Ligands; Light; Link; Mannose; Membrane Microdomains; Mesoderm; Modification; Molecular Genetics; Morphogenesis; Mus; Mutant Strains Mice; Mutate; Mutation; Names; Neuroectoderm; Nodal; Orthologous Gene; Pathway interactions; Pattern; Peptide Signal Sequences; Personal Communication; Phenotype; Portal Hypertension; Positioning Attribute; Post-Translational Protein Processing; Pregnancy; Primitive Streaks; Primitive foregut structure; Prosencephalon; Proteins; Role; Septate; Signal Pathway; Signal Transduction; Site; Sleep; Specific qualifier value; Sphingolipids; Structure; Surface; Testing; Time; Tissues; To specify; Transforming Growth Factor beta; Truncus Arteriosus; Urine; Visceral; activating transcription factor; base; cancer type; cell motility; driving force; embryo tissue; enzyme biosynthesis; gastrulation; gene function; insight; interest; migration; molecular marker; mutant; novel; phosphoethanolamine; portal vein thrombosis; progenitor; programs; prospective; receptor; response; trans-Golgi Network; transcription factor

DESCRIPTION (provided by applicant): Holoprosencephaly (HPE) is a developmental defect of the forebrain, which occurs in 1 out of 250 pregnancies. HPE is characterized by either forebrain truncation or failure of forebrain septation and various other midline defects. In the developing mouse embryo, the forebrain is first specified during gastrulation by the anterior visceral endoderm (AVE), an extra-embryonic tissue. The AVE specifies forebrain in the underlying embryonic tissue by blocking the signals from the primitive streak that provide posterior character to the tissue. As development proceeds, the AVE is displaced by the anterior definitive endoderm (ADE), which also has forebrain specification activity. Cripto, which is expressed in the posterior aspect of the gastrulating embryo, is critically involved in AVE migration and ADE specification. Cripto null embryos have severe gastrulation defects, whereas Cripto hypomorphs have HPE. I have isolated a mouse line, gonzo, that also displays gastrulation and HPE phenotypes. Furthermore, I have mapped the gene responsible for this mutation to a small region of chromosome 1, and have identified a mutation in Pig-N, a GPI-biosynthesis enzyme. Because the phenotypes of Cripto and gonzo mutants are strikingly similar, and because Cripto is a GPI-anchored protein, I will test the following hypotheses: First, HPE results from either an AVE migration defect or failure to specify the ADE. Second, the Pig-N mutation is responsible for the HPE phenotype. Third, aberrant GPI modification of Cripto disrupts Cripto signaling - and is the causative factor for the HPE phenotype. In this proposal I will complete the following aims: Aim 1: I will further characterize the HPE phenotype, and specifically look at specification of the AVE and ADE by examining molecular markers known to be involved in head morphogenesis. Aim 2: I will confirm that the mutation in Pig-N is responsible for the HPE phenotype and determine its effect on Pig-N stability, localization and activity. Aim 3: I will determine Cripto activity in gonzo embryos, and will attempt to rescue the phenotype by artificially targeting Cripto to its site of activation. Holoprosencephaly (which occurs in 1 out of 250 pregnancies) is characterized by forebrain defects; the most severe cases result in a single, cyclopic eye. I have identified a new gene in the mouse that results in holoprosencephaly when it is mutated. This proposal will identify the normal function of this gene thus leading to a better understanding of the causes of holoprosencephaly.

描述（由申请人提供）：前脑畸形（HPE）是一种前脑发育缺陷，250例妊娠中有1例发生。HPE的特征是前脑截断或前脑分隔失败和各种其他中线缺陷。在发育中的小鼠胚胎中，前脑在原肠胚形成过程中首先由前内脏内胚层（AVE）指定，这是一种胚胎外组织。AVE通过阻断来自原始条纹的信号来指定胚胎组织中的前脑，而原始条纹为组织提供了后天性。随着发育的进行，AVE被前决定性内胚层（ADE）取代，后者也具有前脑规范活动。在原肠胚后部表达的Cripto在AVE迁移和ADE规范中起关键作用。隐胚无胚具有严重的原肠胚发育缺陷，而隐胚次胚具有HPE。