Cell Type-Specific Roles of FoxP Transcription Factors in Vocalization and Cognition




Co, Marissa

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Mutations of the forkhead domain transcription factors FOXP2 and FOXP1 are highly associated with neurodevelopmental disorders affecting speech and language. Across vertebrate species, their conserved expression patterns in the developing and adult brain predict important functions in neural circuits mediating vocalization and sensorimotor learning. Their known gene targets regulate neuronal development, activity, and plasticity, and animal models of FoxP2 and FoxP1 function have linked some of these molecular functions with neurophysiological and behavioral phenotypes. Still, much remains unknown about molecular networks in the brain driven by these transcription factors, especially in specific regions and cell types. During my dissertation work, I sought to elucidate FoxP2 and FoxP1 functions in cortical, striatal, and cerebellar neurons in mice and zebra finches. This approach of combining comparative genomics with functional studies of salient genes has proven a powerful method for understanding higher cognitive functions such as language (Chapter Two). By characterizing mice lacking cortical Foxp2, I identified its roles in dopamine signaling, interneuron development, and cognitive behavior, but surprisingly not in vocalization (Chapter Three). I further studied the interaction between FoxP2 and its cortical binding partner TBR1, and I found synergistic gene regulation by these transcription factors in neural cells (Chapter Four). I contributed to identification of roles for cortico-hippocampal FoxP1 in cortical development and vocalization (Chapter Five), as well as roles for cerebellar FoxP2 in Purkinje cell morphology, vocalization, and gross motor function (Chapter Six). Finally, I generated tools and datasets to further our understanding of corticostriatal functions of FoxP2 and FoxP1 in vocal learning zebra finches (Chapter Seven). In light of these studies, I discuss their implications for understanding human disorders affecting speech and language, and I impart further hypotheses and recommendations for continuing their study (Chapter Eight). Together, these findings contribute to our knowledge of conserved roles for FoxP2 and FoxP1 in vocal behavior and cognition.

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