BRCA1 and ELK-1 regulate neural progenitor cell fate in the optic tectum in response to visual experience in Xenopus laevis tadpoles

Significance

Activity in the developing brain affects the fate of multipotent neural progenitor cells, for instance, whether they continue dividing or differentiate into neurons. We conducted an unbiased screen to identify candidate mechanisms that influence neural progenitor cell fate by analyzing differentially expressed transcriptomes from neural progenitor cells and newly differentiated neurons in Xenopus tadpoles following exposure to a visual experience regime known to affect neurogenesis. We identified BRCA1 and ELK-1 as members of a differentially expressed network of transcriptional regulators. Longitudinal in vivo time-lapse imaging indicates that BRCA1 and ELK1 regulate neural progenitor cell fate and that the effects of visual experience on cell fate decisions require BRCA1 and ELK-1. This study expands our understanding of the mechanisms governing brain development.

Abstract

In developing Xenopus tadpoles, the optic tectum begins to receive patterned visual input while visuomotor circuits are still undergoing neurogenesis and circuit assembly. This visual input regulates neural progenitor cell fate decisions such that maintaining tadpoles in the dark increases proliferation, expanding the progenitor pool, while visual stimulation promotes neuronal differentiation. To identify regulators of activity-dependent neural progenitor cell fate, we profiled the transcriptomes of proliferating neural progenitor cells and newly differentiated neurons using RNA-Seq. We used advanced bioinformatic analysis of 1,130 differentially expressed transcripts to identify six differentially regulated transcriptional regulators, including Breast Cancer 1 (BRCA1) and the ETS-family transcription factor, ELK-1, which are predicted to regulate the majority of the other differentially expressed transcripts. BRCA1 is known for its role in cancers, but relatively little is known about its potential role in regulating neural progenitor cell fate. ELK-1 is a multifunctional transcription factor which regulates immediate early gene expression. We investigated the potential functions of BRCA1 and ELK-1 in activity-regulated neurogenesis in the tadpole visual system using in vivo time-lapse imaging to monitor the fate of GFP-expressing SOX2+ neural progenitor cells in the optic tectum. Our longitudinal in vivo imaging analysis showed that knockdown of either BRCA1 or ELK-1 altered the fates of neural progenitor cells and furthermore that the effects of visual experience on neurogenesis depend on BRCA1 and ELK-1 expression. These studies provide insight into the potential mechanisms by which neural activity affects neural progenitor cell fate.