Ongoing roles of Phox2 homeodomain transcription factors during neuronal differentiation

Abstract

Transcriptional determinants of neuronal identity often stay expressed after their downstream genetic program is launched. Whether this maintenance of expression plays a role is for the most part unknown. Here, we address this question for the paralogous paired-like homeobox genes Phox2a and Phox2b, which specify several classes of visceral neurons at the progenitor stage in the central and peripheral nervous systems. By temporally controlled inactivation of Phox2b, we find that the gene, which is required in ventral neural progenitors of the hindbrain for the production of branchio-visceral motoneuronal precursors, is also required in these post-mitotic precursors to maintain their molecular signature - including downstream transcription factors - and allow their tangential migration and the histogenesis of the corresponding nuclei. Similarly, maintenance of noradrenergic differentiation during embryogenesis requires ongoing expression of Phox2b in sympathetic ganglia, and of Phox2a in the main noradrenergic center, the locus coeruleus. These data illustrate cases where the neuronal differentiation program does not unfold as a transcriptional `cascade' whereby downstream events are irreversibly triggered by an upstream regulator, but instead require continuous transcriptional input from it.