Role of FOXR1 in Mammalian Brain Development

 描述（由申请人提供）：NIH的未诊断疾病网络（UDN）已确定一名患者出现重度神经系统症状，包括小头畸形、MRI显示的进行性脑萎缩和整体发育迟缓。UDN在该个体中鉴定出FOXR 1（前额[FH]盒蛋白R1）基因中的特定突变，导致非同义蛋白质改变。FOXR 1是FH转录因子家族的成员，在人类中包含至少50个不同的人类基因。FOXR 1的功能目前尚不清楚;然而，FOX家族中的几个基因，包括FOXG 1和FOXP 2，对神经元和大脑的正常发育至关重要，FOXG 1，FOXC 2和FOXL 2的突变也可能导致小头畸形。基于这些观察结果，本申请的中心假设是FOXR 1是一种核转录因子，在发育中的皮质中的神经元增殖、分化和迁移中发挥核心作用。因此，我们的目标是确定FOXR 1在大脑发育中的作用，并确定FOXR 1功能的分子机制以及FOXR 1突变如何导致疾病的发病机制。通过创新的方法，如分子遗传学，包括ChIP来识别转录靶点和子宫内电穿孔来获得体内数据，拟议的研究将为FOXR 1在大脑发育和疾病发病机制中提供新的见解。此外，这项研究的结果可能揭示了许多与皮质功能相关的神经和精神疾病的病因学机制。

 DESCRIPTION (provided by applicant): The Undiagnosed Disease Network (UDN) of the NIH has identified an individual presenting with severe neurological symptoms including microcephaly, progressive brain atrophy on MRI and global developmental delay. The UDN identified a specific mutation in the FOXR1 (forehead [FH] box protein R1) gene in this individual resulting in a non-synonymous protein alteration. FOXR1 is a member of the FH transcription factor family that in humans comprises at least 50 distinct human genes. The function of FOXR1 is currently unknown; however, several genes within the FOX family including FOXG1 and FOXP2 are critical for proper neuronal and brain development and mutations in FOXG1, FOXC2 and FOXL2 can also lead to microcephaly. Based on these observations, the central hypothesis of this application is that FOXR1 is a nuclear transcription factor that plays a central role in neuronal proliferation, differentiation and migration in the developing cortex. Therefore, our aims are to determine the role of FOXR1 in brain development and determine the molecular mechanism underlying FOXR1 function and how the FOXR1 mutation leads to disease pathogenesis. With innovative approaches such as molecular genetics including ChIP to identify transcriptional targets and in utero electroporation to obtain n vivo data, the proposed research will provide new insights into FOXR1 in brain development and disease pathogenesis. In addition, the results of this study may shed light on mechanisms relevant to the etiology of many neurological and psychiatric disorders related to cortical function.