Binary Fate Choice between Closely Related Interneuronal Types Is Determined by a Fezf1-Dependent Postmitotic Transcriptional Switch

Neuron. 2020 Feb 5;105(3):464-474.e6. doi: 10.1016/j.neuron.2019.11.002. Epub 2019 Dec 4.

Abstract

Many neuronal types occur as pairs that are similar in most respects but differ in a key feature. In some pairs of retinal neurons, called paramorphic, one member responds to increases and the other to decreases in luminance (ON and OFF responses). Here, we focused on one such pair, starburst amacrine cells (SACs), to explore how closely related neuronal types diversify. We find that ON and OFF SACs are transcriptionally distinct prior to their segregation, dendritic outgrowth, and synapse formation. The transcriptional repressor Fezf1 is selectively expressed by postmitotic ON SACs and promotes the ON fate and gene expression program while repressing the OFF fate and program. The atypical Rho GTPase Rnd3 is selectively expressed by OFF SACs and regulates their migration but is repressed by Fezf1 in ON SACs, enabling differential positioning of the two types. These results define a transcriptional program that controls diversification of a paramorphic pair.

Keywords: Fezf1; ON-OFF; Rnd3; amacrine; cell fate; migration; polarization; retina; starburst; transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amacrine Cells / chemistry
  • Amacrine Cells / metabolism*
  • Animals
  • Animals, Newborn
  • Female
  • HEK293 Cells
  • Humans
  • Interneurons / chemistry
  • Interneurons / metabolism*
  • Mice
  • Mice, 129 Strain
  • Mice, Transgenic
  • Mitosis / physiology*
  • Pregnancy
  • Repressor Proteins / analysis
  • Repressor Proteins / biosynthesis*
  • Repressor Proteins / genetics*
  • Transcription, Genetic / physiology*

Substances

  • Fezf1 protein, mouse
  • Repressor Proteins