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

自闭症是一种常见的儿童疾病，每1000名儿童中约有3.4人患有自闭症，需要终生护理，这给家庭和国家机构带来了沉重的负担。ASD的核心特征包括社交、沟通和行为方面的缺陷，并可出现其他共病，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病例是复杂的和散发性的，有多种因素结合在一起产生疾病表型；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ASD之间存在遗传异质性，但这些疾病表现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，因果突变跨障碍、漏斗通过常见的分子途径，从而表明可推广治疗的可能性。目前，药物治疗严重缺乏，因为目前还没有有效的药理学药物来治疗ASD的核心症状。因此，需要对ASD的神经生物学和潜在的病理生理学进行进一步的研究。在我们的资助中，我们建议通过发展ASD风险基因的细胞和动物模型来建立ASD模型 转录因子4(TCF4)发生突变。TCF4与一种罕见的神经发育模型PITT有关 表现出自闭症特征的霍普金斯综合征(PTHS)。我们希望通过对这种疾病进行建模，我们可以确定 与ASD风险相关的细胞和分子机制最终将导致发现 治疗性干预。 在目标1中，我们证明了TCF4调节少突胶质细胞(OL)的发育和在 TCF4可导致髓鞘过少。我们来自突变的TCF4小鼠模型的初步数据表明，TCF4 调节少突胶质前体细胞(OPC)向成熟OL的分化，从而导致 髓鞘形成显著减少。我们建议进行实验，以确定细胞和分子机制 TCF4如何调控OPC分化。在目标2中，我们提出了连接依赖TCF4的实验 特异地调控TCF4表达的下髓鞘对生理和行为缺陷的影响 OL血统。此外，我们建议通过生后恢复来挽救生理和行为缺陷 TCF4仅在OL谱系中表达，以确定这种靶向挽救髓鞘是否可以导致 生理和行为缺陷的正常化。在目标3中，我们建议使用PTHS患者来源的 诱导多能干细胞(IPSCs)以确定在我们的小鼠中观察到的OPC分化表型 模型转化为人类的疾病模型。总而言之，这些目标旨在确定治疗方法 PTHS和潜在的其他ASD的治疗目标。

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.