Mouse models of human cerebellar malformations

与其他大脑相比，人类小脑的发育缺陷受到的关注较少 神经管缺陷和皮质畸形等畸形。然而，小脑畸形是 这很常见，影响了大约1/5000的新生儿。Dandy-Walker畸形(DWM)与小脑疣 发育不全(CVH-也称为Dandy-Walker变异)是最常见的小脑畸形， 受影响的人通常有运动障碍、智力低下，还有一些人患有脑积水。虽然 这些临床上重要的出生缺陷的具体原因在很大程度上仍未确定，有证据表明 相当大的遗传异质性和复杂的遗传。基于染色体的物理图谱 在患者的异常中，我们已经确定了3个含有人类小脑畸形基因的基因：ON 染色体3q24、6p25和7q36。这项提案描述了一系列旨在 了解导致小脑和后颅窝结构的发育机制 通过对几个小鼠模型的研究，发现了与这些基因座相关的异常。 我们先前已经证明，紧密连锁的ZIC1/4基因杂合性共缺失 染色体3q24引起弥漫性肌萎缩侧索硬化。这项提案的目标1描述了在小鼠身上进行的一系列遗传学实验 评估这些ZIC基因调控的发育途径，并进行一系列体外分析以确定 Zic1和Zic4蛋白相互作用的物理性质是观察到的遗传相互作用的基础。这个 Aim 2中的实验旨在通过对6p25 DWM的表型表征来定义其基础 影响后颅窝间充质的候选基因的空突变和条件性突变 和小脑发育。此外，还将评估3q24和6p25基因座之间的遗传交互作用。 最后，目标3描述了一系列转基因实验，以确定基因(S)和潜在的 7q36基因小重复导致严重脑血管病患者的发育障碍。自.以来 小鼠和人类中枢神经系统发育的机制相似，分析这些小鼠将 确定人类小脑畸形的潜在分子和发育原因。这 信息对于识别额外的畸形位点是至关重要的。

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) and cerebellar vermis hypoplasia (CVH- also known as Dandy-Walker Variant) are the most frequent cerebellar malformations, and affected individuals often have motor deficits, mental retardation, and some have hydrocephalus. Although the specific causes of these clinically important birth defects 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 3 loci harboring human cerebellar malformation genes: on chromosomes 3q24, 6p25 and 7q36. This proposal describes a series of experiments aimed at understanding the developmental mechanisms leading to the structural cerebellar and posterior fossa abnormities associated with these loci 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 mice to assess the developmental pathways regulated by these Zic genes and a set of in vitro analyses to determine the physical nature of Zic1and Zic4 protein interactions underlying the observed genetic interaction. 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. Further, genetic interactions between the 3q24 and 6p25 loci will be assessed. Finally, Aim 3 describes a series of transgenic experiments to determine the gene(s) and underlying developmental disruption causing severe CVH in a patient with a small genomic duplication of 7q36. 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 cerebellar malformations. This information is critical to the identification of additional malformation loci.