Journal Article

Foxp2 mutations and abnormal brain and gastrointestinal development: insights from animal models of speech-language and autism spectrum disorders

Momoi, Takashi, Fujita-Jimbo, Eriko, Kawahara, Genri

2026

Overview

Autism spectrum disorder (ASD) and speech and language disorder (SLD) are distinct neurodevelopmental conditions, yet both share overlapping communication impairments. Forkhead box P2 ( FOXP2 ), a key transcription factor involved in speech and language development, harbors pathogenic mutations such as R553H, which cause SLD and have been suggested to contribute to aspects of ASD-related phenotypes. This review synthesizes insights from animal models to explore the molecular mechanisms by which Foxp2 mutations disrupt the development of the cerebral cortex, thalamus, and enteric nervous system. We highlight findings from heterozygous Foxp2 mutants and discuss severe phenotypes observed in homozygous Foxp2 mutants ( Foxp 2 R552H/R552H and Foxp 2 R552H/R552H /mCherry-Tg mice), including profound ultrasonic vocalization deficits, brain malformations, and early lethality. Notably, these mice exhibit gastrointestinal abnormalities involving the epithelium, smooth muscle, and enteric nervous system, which are linked to impaired autoregulation and interference with Wnt signaling during development. Such observations underscore the relevance of the brain–gut–microbiome axis and Hirschsprung-like pathology in neurodevelopmental disorders. Finally, this review discusses future directions using gene-editing approaches in non-mammalian models—zebra finches, zebrafish, and Drosophila —to dissect neural networks underlying intellectual disability and communication deficits. Collectively, these studies provide a framework for understanding FOXP2 -related molecular mechanisms in the pathogenesis of ASD and SLD.

• Publisher: Frontiers Research Foundation,Frontiers Media SA,Frontiers Media S.A
• Subject: Animal models / Autism / autism spectrum disorder (ASD) / brain-gut-microbiome axis / Cerebral cortex / cerebral cortex development / Enteric nervous system / Epithelium / Forkhead protein / Forkhead-box Protein P2 (FOXP2) / Foxp2 protein / Intellectual disabilities / Language / Lethality / Microbiomes / Molecular modelling / Mutants / Mutation / Nervous system / Neural networks / Neurodevelopmental disorders / Phenotypes / Review / Smooth muscle / Speech / speech and language disorder (SLD) / Vocalization behavior / Wnt protein