FOXP transcription factors in vertebrate brain development, function, and disorders

Abstract

FOXP transcription factors are an evolutionarily ancient protein subfamily coordinating the development of several organ systems in the vertebrate body. Association of their genes with neurodevelopmental disorders has sparked particular interest in their expression patterns and functions in the brain. Here, FOXP1, FOXP2, and FOXP4 are expressed in distinct cell type‐specific spatiotemporal patterns in multiple regions, including the cortex, hippocampus, amygdala, basal ganglia, thalamus, and cerebellum. These varied sites and timepoints of expression have complicated efforts to link FOXP1 and FOXP2 mutations to their respective developmental disorders, the former affecting global neural functions and the latter specifically affecting speech and language. However, the use of animal models, particularly those with brain region‐ and cell type‐specific manipulations, has greatly advanced our understanding of how FOXP expression patterns could underlie disorder‐related phenotypes. While many questions remain regarding FOXP expression and function in the brain, studies to date have illuminated the roles of these transcription factors in vertebrate brain development and have greatly informed our understanding of human development and disorders. This article is categorized under: Nervous System Development > Vertebrates: General Principles Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Nervous System Development > Vertebrates: Regional Development

Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities

“…Importantly, FOXP4 is not only expressed in adult tissue, but also during different stages of development of, e.g., the heart, lungs, gut, and skeleton, where it has been shown to play important functional roles. 2,[32][33][34][35] This widespread expression pattern, in combination with the large number of transcriptional targets and protein-protein interactions known for FOXP transcription factors, 10,[36][37][38] could potentially yield a large variety of downstream consequences when FOXP4 functions are compromised. It is thus not surprising that we found a broad range of associated phenotypes in individuals with likely pathogenic FOXP4 variants, including growth deficits, developmental delays and a spectrum of associated congenital abnormalities.…”

“…Of note, in FOXP1and FOXP2-related disorders, expressive speech problems are a prominent feature, 40 and the contributions of these regulatory factors to the development and function of relevant neural circuits are extensively studied. 10,42 A recent study linking FoxP1/2/4 functions to vocal learning in songbirds suggested that FOXP4 should also be considered as a candidate for involvement in vocal disorders. 43 Indeed, all individuals with likely pathogenic FOXP4 variants in our study had delayed speech/language development, with expressive problems prominently present.…”

“…2,7 The encoded protein has regulatory roles in the development and maturation of the central nervous system. 8,9 It is coexpressed with FOXP1 and/or FOXP2 in several different brain regions, such as the cortex, cerebellum, and striatum, 10 where these transcription factors may heterodimerize, to potentially coregulate downstream targets. The phenotype associated with heterozygous germline FOXP4 variants remains to be defined.…”

Identification ofFoxPcircuits involved in locomotion and object fixation inDrosophila

“…Moreover, the PB provides input to other components of the central complex involved in angular orientation (Kim et al, 2019;Kottler et al, 2019;Seelig and Jayaraman, 2015;Su et al, 2017). (Co et al, 2020;Lu et al, 2002;Shu et al, 2007). What is less well known is if adult FoxP expression serves any specific function.…”

“…In mammals, the FoxP subfamily (FoxP1-4) members (Santos et al, 2011) are abundantly expressed during the development of multiple cell types, such as cardiomyocytes, neurons, lung epithelial secretory cells and T-cells (Golson and Kaestner, 2016). In particular, FoxP1 and FoxP2 have generated interest because of their roles in regulating the development of cognitive processes such as speech and language acquisition (Bolhuis, 2011;Carr et al, 2010;Co et al, 2020;den Hoed and Fisher, 2020;Hagoort, 2019;Horn et al, 2010;Lai et al, 2001;Morgan et al, 2016;Reuter et al, 2017;Schatton and Scharff, 2016).…”