TheIroquois(Iro/Irx) homeobox genes are conserved Hox targets involved in motor neuron development

Abstract

TheIroquois (Iro/Irx)homeobox genes encode transcription factors with fundamental roles in animal development. Despite their link to various congenital conditions in humans, our understanding ofIro/Irxgene expression, function, and regulation remains incomplete. Here, we conducted a systematic expression analysis of all six mouseIrxgenes in the embryonic spinal cord. We found fiveIrxgenes (Irx1, Irx2, Irx3, Irx5,andIrx6) to be confined mostly to ventral spinal domains, offering new molecular markers for specific groups of post-mitotic motor neurons (MNs). Further, we engineeredIrx2, Irx5,andIrx6mouse mutants and uncovered essential but distinct roles forIrx2andIrx6in MN development. Last, we found that the highly conserved regulators of MN development across species, the HOX proteins, directly controlIrxgene expression both in mouse andC. elegansMNs, critically expanding the repertoire of HOX target genes in the developing nervous system. Altogether, our study provides important insights intoIro/Irxexpression and function in the developing spinal cord, and uncovers an ancient gene regulatory relationship between HOX andIro/Irxgenes.