The neural underpinnings of vocal communication remain mostly unknown. The long-term goal of our laboratory is to elucidate the molecular signaling pathways important in vocal communication that are disrupted in neurodevelopmental disorders. Mutations in the gene encoding FOXP2 have previously been identified in individuals with speech and language disorders. In addition, FOXP2 transcriptionally regulates many genes involved in neurodevelopmental disorders such as autism and schizophrenia. Our preliminary studies have shown that expression of FOXP2 in the cerebellum is important for normal vocalizations and motor function. Moreover, we have uncovered a conserved site of post-translational modification of FOXP2 that it is important for gene expression regulation and motor function. Based on these data, the central hypothesis driving this proposal is that post-translational modification of FOXP2 is critical for regulating vocalizations and motor function. We propose to identify the role of post-transcriptional modification of FOXP2 on cerebellar-specific gene expression and motor function by manipulating Foxp2 expression in the mouse cerebellum through four specific aims: 1) Determine whether Foxp2 expression in the developing cerebellum is important for vocalizations and gene expression; 2) Assess the role of post-translational modification of Foxp2 on vocalizations; 3) Determine the role of post-translational modification of Foxp2 on gene expression; and 4) Assess the role of post-translational modification of Foxp2 on motor function. Together, these aims will determine the transcriptional program regulated by Foxp2 in the cerebellum and how Foxp2 gene regulation may be related to vocalizations and other motor-relevant behaviors. Completion of the proposed aims will provide increased knowledge as to the molecular pathways that can be targeted for treatment in individuals with communication disorders, cerebellar based motor disorders, and autism, which involves disrupted cerebellar function. These data will also provide insight into the basic molecular mechanisms governing normal brain development.

Public Health Relevance

Dysfunction in the cerebellum is associated with many brain disorders including autism and ataxia. Understanding the genes and molecular pathways critical for normal cerebellar development will provide insight into the etiology of many brain disorders as well as the normal development of vocalizations and other motor behaviors. These proposed studies will elucidate genes and molecular pathways specifically important for cerebellar development that can be targeted for the treatment autism, ataxias, or disorders with a speech and language component in future studies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC014702-03
Application #
9390469
Study Section
Motor Function, Speech and Rehabilitation Study Section (MFSR)
Program Officer
Shekim, Lana O
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Usui, Noriyoshi; Co, Marissa; Harper, Matthew et al. (2017) Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development. Biol Psychiatry 81:220-230
Usui, Noriyoshi; Araujo, Daniel J; Kulkarni, Ashwinikumar et al. (2017) Foxp1 regulation of neonatal vocalizations via cortical development. Genes Dev 31:2039-2055
Araujo, Daniel J; Toriumi, Kazuya; Escamilla, Christine O et al. (2017) Foxp1 in Forebrain Pyramidal Neurons Controls Gene Expression Required for Spatial Learning and Synaptic Plasticity. J Neurosci 37:10917-10931
Konopka, Genevieve; Roberts, Todd F (2016) Insights into the Neural and Genetic Basis of Vocal Communication. Cell 164:1269-1276