Mouse models of human cerebellar malformations

: 人类小脑的发育缺陷比其他大脑发育缺陷受到的关注少 畸形如神经管缺陷和皮质畸形。然而，小脑畸形是 常见，影响约1/5000出生。Dandy-Walker畸形（DWM）是最常见的 小脑畸形受影响的个体通常具有运动缺陷、精神发育迟滞、自闭症和一些其他疾病。 患有脑积水虽然这种临床上重要的出生缺陷的具体原因仍然主要是 虽然没有明确的定义，但有证据表明存在相当大的遗传异质性和复杂的遗传。基于 通过对患者染色体异常的物理作图，我们鉴定了2个携带人类DWM的基因座 在染色体3q 24和6p 25上。这份提案描述了一系列旨在了解 通过对几种小鼠模型的研究，探讨导致DWM病理学的发育机制。 我们以前已经证明，在正常人中紧密连锁的ZIC 1/4基因的杂合共缺失， 染色体3q 24引起DWM。本提案的目的1描述了Zic 1/4中的一系列遗传实验 突变小鼠，以评估这些Zic基因调控的发育途径。目标2中的实验 设计用于定义6p 25 DWM的基础，通过无效和 影响后颅窝间充质和小脑的候选基因的条件性小鼠突变体 发展由于小鼠和人CNS发育的基础机制相似，因此对这些机制的分析是必要的。 小鼠将确定人类DWM的潜在分子和发育原因。该信息 这对鉴定其他人DWM基因座至关重要。

: Developmental defects of the cerebellum in humans have received less attention than other brain malformations such as neural tube defects and cortical malformations. Yet, cerebellar malformations are common, affecting approximately 1/5000 births. Dandy-Walker Malformation (DWM) is the most frequent cerebellar malformation. Affected individuals often have motor deficits, mental retardation, autism and some have hydrocephalus. Although the specific causes of this clinically important birth defect remain largely undefined, there is evidence for considerable genetic heterogeneity and complex inheritance. Based on physical mapping of chromosomal abnormalities in patients, we have identified 2 loci harboring human DWM on chromosomes 3q24 and 6p25. This proposal describes a series of experiments aimed at understanding the developmental mechanisms leading to DWM pathology through the study of several mouse models. We have previously demonstrated that heterozygous co-deletion of the closely linked ZIC1/4 genes on chromosome 3q24 causes DWM. Aim 1 of this proposal describes a series of genetic experiments in Zic1/4 mutant mice to assess the developmental pathways regulated by these Zic genes. The experiments in Aim 2 are designed to define the basis of 6p25 DWM, through phenotypic characterization of both null and conditional mouse mutants of a candidate gene influencing both posterior fossa mesenchymal and cerebellar development. Since similar mechanisms underlie both mouse and human CNS development, analysis of these mice will to determine the underlying molecular and developmental causes of human DWM. This information is critical to the identification of additional human DWM loci.