Functional characterization of the transcription factor FOXP1 and its target genes in cognitive development

言语和语言障碍的特征是流利、可理解语言的习得受损，有时与其他发育障碍（如智力障碍）共存。智力残疾是一种广泛的发育障碍，其特征是智力能力有限（IQ <70）。对于许多患者来说，语言障碍和智力残疾都是由遗传缺陷引起的。与语言障碍相关的第一个也是最著名的基因是叉头盒P2（FOXP 2）基因。FOXP 2是叉头框转录因子FOXP-亚家族的四个成员之一。在最近的一项研究中，我们确定了相关FOXP 1基因的缺失在三个智力残疾和言语和语言能力的显着损害的患者。这一发现表明转录因子FOXP 1与FOXP 2非常相似，可能在脑发育过程中发挥重要作用。与F0 XP 2不同，F0 XP 1如何调节这些过程知之甚少。我们项目的目标是描述F0 XP 1在大脑发育中的作用，并确定代表该蛋白在神经元分化中的下游靶点的基因。我们的主要目的是产生一个条件Foxp 1基因敲除小鼠，其中Foxp 1是删除专门在中枢神经系统，以避免胚胎死亡的Foxp 1常规基因敲除小鼠在胚胎天（E）14.5由于心脏缺陷。我们将使用这种条件性敲除来研究在Foxp 1缺失的情况下的大脑发育，并确定Foxp 1的靶点。

Speech and language disorders are characterized by an impaired acquisition of fluent, comprehensible language and sometimes co-segregate with other developmental disorders such as intellectual disability. Intellectual disability is a widespread developmental disorder characterized by limitations in intellectual abilities (IQ <70). For many patients, both language disorders and intellectual disability are caused by genetic defects. The first and best known gene associated with language disorders is the Forkhead Box P2 (F0XP2) gene. F0XP2 is one of four members of the FOXP ¬-subfamily of forkhead box transcription factors. In a recent study, we identified deletions of the related FOXP1 gene In three patients with intellectual disability and significant impairment of speech and language abilities. This finding indicated that the transcription factor FOXP1, very similar to FOXP2, might play an important role during brain development. Unlike F0XP2, very little is known about how F0XP1 regulates these processes. The goal of our project is to characterize the role of F0XP1 in brain development and to identify the genes that represent the downstream targets of this protein in neuronal differentiation. Our main aims are to generate a conditional Foxp1 knockout mouse, where Foxp1 is deleted specifically in the central nervous system, to sidestep the embryonic lethality of Foxp1 conventional knockout mice at embryonic day (E) 14.5 due to heart defects. We will use this conditional knockout to investigate brain development in the absence of Foxp1 and to identify targets of Foxp1.