PT  - JOURNAL ARTICLE
AU  - Huihui Qi
AU  - Li Luo
AU  - Caijing Lu
AU  - Runze Chen
AU  - Xianyao Zhou
AU  - Xiaohui Zhang
AU  - Yichang Jia
TI  - TCF7L2 acts as a molecular switch in midbrain to control mammal vocalization through a transcriptional repression mechanism
AID  - 10.1101/2022.01.10.475593
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.10.475593
4099  - http://biorxiv.org/content/early/2022/01/11/2022.01.10.475593.short
4100  - http://biorxiv.org/content/early/2022/01/11/2022.01.10.475593.full
AB  - Vocalization is an essential medium for sexual and social signaling in birds and mammals. Periaqueductal gray (PAG) a conserved midbrain structure is believed to be responsible for innate vocalizations, but its molecular regulation remains largely unknown. Here, through a mouse forward genetic screening we identified one of the key Wnt/ β-catenin effectors TCF7L2/TCF4 controls ultrasonic vocalization (USV) production and syllable complexity during maternal deprivation and sexual encounter. Expression of TCF7L2 in PAG excitatory neurons is necessary for the complex trait, while TCF7L2 loss reduces neuronal gene expressions and synaptic transmission in PAG. TCF7L2-mediated vocal β-catenin-binding domain but dependent of its DNA binding ability. Patient mutations associated with severe speech delay disrupt the transcriptional repression effect of TCF7L2, while mice carrying those mutations display severe USV impairments. Therefore, we conclude that TCF7L2 orchestrates gene expression in midbrain to control vocal production through a transcriptional repression mechanism.Competing Interest StatementThe authors have declared no competing interest.