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

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 amacri...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2020-02, Vol.105 (3), p.464-474.e6
Main Authors: Peng, Yi-Rong, James, Rebecca E., Yan, Wenjun, Kay, Jeremy N., Kolodkin, Alex L., Sanes, Joshua R.
Format: Article
Language:English
Subjects:
amacrine
Amacrine cells
Amacrine Cells - chemistry
Amacrine Cells - metabolism
Animals
Animals, Newborn
cell fate
Female
Fezf1
Gene expression
Guanosine triphosphatases
HEK293 Cells
Humans
Interneurons - chemistry
Interneurons - metabolism
Mice
Mice, 129 Strain
Mice, Transgenic
migration
Mitosis - physiology
ON-OFF
polarization
Pregnancy
Repressor Proteins - analysis
Repressor Proteins - biosynthesis
Repressor Proteins - genetics
Retina
Rnd3
starburst
Synaptogenesis
Transcription
transcription factor
Transcription, Genetic - physiology
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Summary: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. [Display omitted] •ON and OFF SACs are transcriptionally distinct prior to migration•Fezf1 is selectively expressed by newly postmitotic ON SACs•Fezf1 functions as a fate switch by activating ON and repressing OFF SAC genes•Rnd3 acts downstream of Fezf1 to enable distinct positioning of ON and OFF SACs Two related retinal cell types called ON and OFF starburst amacrines migrate to distinct laminae and signal increased (ON) or decreased (OFF) illumination. Fezf1 acts as a fate switch between the two types by activating ON and repressing OFF genes.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2019.11.002