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Dev Biol 2017 Nov 15;4312:152-167. doi: 10.1016/j.ydbio.2017.09.027.
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Six1 and Eya1 both promote and arrest neuronal differentiation by activating multiple Notch pathway genes.

Riddiford N , Schlosser G .

The transcription factor Six1 and its cofactor Eya1 are important regulators of neurogenesis in cranial placodes, activating genes promoting both a progenitor state, such as hes8, and neuronal differentiation, such as neurog1. Here, we use gain and loss of function studies in Xenopus laevis to elucidate how these genes function during placodal neurogenesis. We first establish that hes8 is activated by Notch signaling and represses neurog1 and neuronal differentiation, indicating that it mediates lateral inhibition. Using hes8 knockdown we demonstrate that hes8 is essential for limiting neuronal differentiation during normal placode development. We next show that Six1 and Eya1 cell autonomously activate both hes8 and neurog1 in a dose-dependent fashion, with increasing upregulation at higher doses, while neuronal differentiation is increasingly repressed. However, high doses of Six1 and Eya1 upregulate neurog1 only transiently, whereas low doses of Six1 and Eya1 ultimately promote both neurog1 expression and neuronal differentiation. Finally, we show that Six1 and Eya1 can activate hes8 and arrest neuronal differentiation even when Notch signaling is blocked. Our findings indicate that Six1 and Eya1 can both promote and arrest neuronal differentiation by activating the Notch pathway genes neurog1 and hes8, respectively, revealing a novel mechanism of Six1/Eya1 action during placodal neurogenesis.

PubMed ID: 28947179
Article link: Dev Biol

Species referenced: Xenopus laevis
Genes referenced: dll1 eya1 hes2 hes4 hes5.2 hes5.4 hes5.7 hes6.1 hes7.1 isl2 myc neurod1 neurog1 neurog2 nodal notch1 pax3 pou4f1 pou4f4 six1 sox2 sox21 sox3 tubb2b
GO keywords: Notch signaling pathway [+]
Morpholinos: eya1 MO1 eya1 MO2 hes5.4 MO1 six1 MO1 six1 MO2

Article Images: [+] show captions