Dissecting the pan-placodal gene regulatory network reveals novel interactions driving sense organ development in vertebrates

Abstract

The genes encoding the transcription factor Six1, and its co-factor Eya1 together mark the embryonic territory - the pan-placodal ectoderm (PPE) - that gives rise to most cranial sense organs in vertebrates. Mutation of these genes gives rise to severe craniofacial defects, and they are implicated in the progression of a range of cancers. However, how Six1 and Eya1 regulate such processes is unclear. This study reveals the direct targets of Six1 and Eya1 in the PPE, and further verifies and characterises a subset of these to elucidate important, and novel, regulatory interactions underlying sense organ formation. The direct targets revealed in this study are involved in both the proliferation (including Hes5/8, Hes9, Sox2 and Sox3) and differentiation (including Ngn1, Atoh1, Pou4f1.2, Isl2, Gfi1a and Tlx1) of neuronal progenitors, and this study provides compelling evidence that Six1 and Eya1 directly affect both processes. Additionally, this study demonstrates that overexpression of Six1 and Eya1 inhibits neuronal differentiation in a Notch-independent way, by directly activating Hes5/8, suggesting a likely mechanism through which Six1 and Eya1 promote proliferation in neuronal progenitors. Finally, this study proposes a model of gene regulation in the PPE, whereby Six1 and Eya1 synergistically regulate a complex gene regulatory network underlying the development of sense organs in vertebrates.