FOXP1 differentially regulates the development of murine vasopressin and oxytocin magnocellular neurons

Abstract

The neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) are closely related. As neurohormones, AVP and OXT are mainly produced in magnocellular neurons (MCNs) located in the hypothalamus. Development of both neuron types requires coordinated expression of transcription factors OTP, SIM1, ARNT2 and POU3F2. However, the exact transcription factors involved in the diferential diferentiation of the AVP and OXT lineages are yet unknown. We used a publicly available single-cell RNA-sequencing dataset of the developing mouse hypothalamus to identify gene regulatory networks linked to AVP and OXT neuronal diferentiation. We identified RORA, EBF3, FOXP1, FOXP2, and BCL11B as transcription factors with possible relevance for Avp and Oxt MCN divergence. We then modeled developmental gene expression dynamics using computational cell fate mapping. This revealed enrichment of EBF3 and BCL11B in the Avp lineage, while FOXP1 and FOXP2 are enriched in the Oxt lineage. Next, in silico analysis of Avp and Oxt promoters found predicted binding sites for FOXP1 and FOXP2 in the Oxt promoter, suggesting a role in Oxt MCN diferentiation. Finally, we validated the role of one candidate (FOXP1) with a heterozygous knockout mouse line. Compared to wild-type littermates, we find decreased AVP and OXT neuron abundance, with OXT neurons disproportionally afected.