Wild-type huntingtin in neurodevelopment

Huntingtin (HTT) is an essential pleiotropic gene. Primarily known for its pathogenic role in Huntington's disease (HD), a progressive autosomal dominant neurodegenerative disorder. HD is caused by a CAG expansion located in HTT exon 1 that produces an altered protein product, mutant huntingtin, with an expanded polyglutamine stretch. Despite its monogenic origin, HD has a complex cellular pathology likely due to huntingtin's many protein-protein interactions and diverse functional roles. Wild-type huntingtin loss-of-function may influence HD pathogenesis by intertwining with multiple forms of mutant huntingtin gain-of-function toxicity. Multiple studies have identified irregular neurodevelopmental phenotypes in HD models similar to those due to wild-type huntingtin loss-of-function. Current huntingtin lowering treatment developments suggest that a better understanding of normal HTT functions may be vital for effective therapeutic development. Due to the history of huntingtin gene discovery, most previous reviews have focused on the wild-type huntingtin allele in the context of also inheriting the mutant huntingtin allele. The purpose of this review is to explore wild-type huntingtin's putative function, expression, and variation in neurodevelopment in the absence of the mutant HTT allele, providing a basis to better understand how changes in wild-type huntingtin function may play a role in human health and disease.