Abstract
FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells.
Highlights
Mutations in the FOXP2 gene are known to cause rare forms of speech and language disorder, the first report of which was the KE family in 2001 (Lai et al, 2001)
We set out to test whether FOXP2 could drive similar gene expression changes when the cells were maintained in normal growth media
In this study we demonstrate the importance of FOXP2 for human neuronal differentiation using a neuron-like model system
Summary
Mutations in the FOXP2 gene are known to cause rare forms of speech and language disorder, the first report of which was the KE family in 2001 (Lai et al, 2001). Developmentally expressed in many tissues including the brain, lung, and heart, reduced levels of functional FOXP2 results in a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits in patients (Vargha-Khadem et al, 1995; Alcock et al, 2000; Watkins et al, 2002a). This highly specific phenotype suggests that particular aspects of the nervous system have a lower tolerance for FOXP2 reduction than other tissues, such as the heart or lung. The activity of FOXP2 in a subset of neurons throughout the brain is thought to be essential for the proper development of neural networks important for normal speech and language
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