Cellular and Molecular Analysis of the Psychiatric Risk Gene Transcription Factor 4 (TCF4)

ASD是一种常见的儿童疾病，每1,000名儿童中约有3.4名发生，需要终生护理，给家庭和国家机构带来沉重负担。ASD的核心特征包括社会化，沟通和行为缺陷，并可能与其他合并症，如智力残疾，癫痫，焦虑，抑郁，注意力缺陷和睡眠障碍。大多数ASD病例是复杂的，并被分类为散发性的，具有多种因素，这些因素联合收割机组合以产生疾病表型;然而，大约20%的ASD病例是具有明确遗传原因的综合征。尽管不同类型的综合征型ASD之间存在遗传异质性，但这些疾病显示出令人难以置信的表型重叠。这种重叠可能表明，在神经元发育过程中，疾病之间的因果突变通过共同的分子途径汇集，从而表明可推广的治疗的潜力。目前，药物治疗严重缺乏，因为目前不存在有效的药理学试剂来治疗核心ASD症状。因此，需要进一步研究ASD的神经生物学和基础病理生理学。在我们的资助中，我们建议通过开发细胞和动物模型来模拟ASD，其中ASD风险基因 转录因子4（TCF 4）突变。TCF 4与一种称为Pitt的罕见神经发育模型相关 霍普金斯综合征（PTHS），表现出自闭症特征。我们希望通过模拟这种紊乱， 与ASD风险相关的细胞和分子机制，最终将导致发现 治疗干预。 在目标1中，我们证明了Tcf 4调节少突胶质细胞（OLs）的发育和Tcf 4基因突变。 tcf 4导致髓鞘形成不足。我们从突变Tcf 4小鼠模型获得的初步数据表明，Tcf 4 调节少突胶质细胞前体细胞（OPCs）分化为成熟的OL，这导致 髓鞘形成显著减少。我们提出实验来确定细胞和分子机制， Tcf 4如何调节OPC分化。在目标2中，我们提出了将Tcf 4依赖性 通过特异性操纵Tcf 4表达， OL血统。此外，我们建议通过出生后恢复 Tcf 4仅在OL-谱系中表达，以确定这种髓鞘形成的靶向拯救是否可以导致 生理和行为缺陷正常化。在目标3中，我们建议使用PTHS患者衍生的 诱导多能干细胞（IPSC），以确定在我们小鼠中观察到的OPC分化表型 模型转化为人类疾病模型。总之，这些目标旨在确定治疗 治疗PTHS和潜在的其他ASD的靶点。

ASD is a common childhood disorder, which occurs in approximately 3.4 out of every 1,000 children, and requires a lifetime of care that leads to a significant burden for both families and state agencies. Core features of ASD include deficits in socialization, communication and behavior, and can present with other comorbidities such as intellectual disability, epilepsy, anxiety, depression, attention deficits and sleep disorders. The majority of ASD cases are complex and classified as sporadic, having a multitude of factors that combine to produce a disease phenotype; however, approximately 20% of ASD cases are syndromic with a well-established genetic cause. Despite the genetic heterogeneity between different types of syndromic ASD, these disorders display an incredible amount of phenotypic overlap. This overlap may indicate that the causal mutations across disorders, funnel through common molecular pathways during neuronal development, and thus indicate the potential for generalizable treatments. Currently, pharmacotherapies are severely lacking, as no effective pharmacological agents currently exist to treat core ASD symptoms. Therefore, further research into the neurobiology and underlying pathophysiology of ASD is required. In our grant, we propose to model ASD by developing cell and animal models in which the ASD risk gene transcription factor 4 (TCF4) is mutated. TCF4 is associated with a rare neurodevelopmental model called Pitt Hopkins Syndrome (PTHS) that displays autism features. We hope by modeling this disorder we can identify cellular and molecular mechanisms associated with risk for ASD that will eventually lead to the discovery of therapeutic interventions. In Aim 1, we demonstrate that Tcf4 regulates the development of oligodendrocytes (OLs) and mutations in Tcf4 result in hypomyelination. Our preliminary data from a mutant Tcf4 mouse model suggests that Tcf4 regulates the differentiation of oligodendrocyte precursor cells (OPCs) into mature OLs and this leads to a significant decrease in myelination. We propose experiments to identify cellular and molecular mechanism for how Tcf4 regulates OPC differentiation. In Aim 2, we propose experiments to connect Tcf4-dependent hypomyelination to physiological and behavioral deficits by specifically manipulating Tcf4 expression only in the OL-lineage. Moreover, we propose to rescue physiological and behavioral deficits by postnatally reinstating Tcf4 expression only in the OL-lineage to determine if this target rescue of myelination can lead to normalization of physiological and behavioral deficits. In Aim 3, we propose to use PTHS patient-derived induce pluripotent stem cells (IPSCs) to determine if OPC differentiation phenotypes observed in our mouse models translate into human models of disease. Together, these Aims are designed to identify therapeutic targets for the treatment of PTHS and potentially other ASDs.