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Neurod6 expression defines new retinal amacrine cell subtypes and regulates their fate

Abstract

Most regions of the CNS contain many subtypes of inhibitory interneurons with specialized roles in circuit function. In the mammalian retina, the 30 subtypes of inhibitory interneurons called amacrine cells (ACs) are generally divided into two groups: wide/medium-field GABAergic ACs and narrow-field glycinergic ACs, which mediate lateral and vertical interactions, respectively, within the inner plexiform layer. We used expression profiling and mouse transgenic lines to identify and characterize two closely related narrow-field AC subtypes. Both arise postnatally and one is neither glycinergic nor GABAergic (nGnG). Two transcription factors selectively expressed by these subtypes, Neurod6 and special AT-rich-sequence-binding protein 2 (Satb2), regulate a postmitotic cell fate choice between these subtypes. Satb2 induces Neurod6, which persists in nGnG ACs and promotes their fate but is downregulated in the related glycinergic AC subtype. Our results support the view that cell fate decisions made in progenitors and their progeny act together to diversify ACs.

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Figure 1: nGnG ACs.
Figure 2: Transcriptional profiling of MP-line CFP+ ACs and bipolar cells.
Figure 3: Morphology and development of nGnG ACs.
Figure 4: Neurod6 regulated the nGnG versus glycinergic fate decision.
Figure 5: Satb2 and Ebf3 marked nGnG ACs and a related glycinergic subtype.
Figure 6: Neurod6 controlled a postmitotic choice between nGnG and SEG fates.
Figure 7: Satb2 promoted the nGnG fate by inducing Neurod6.

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Acknowledgements

We thank R. Reed (Johns Hopkins University) for providing anti-Ebf, D. Pow (University of Queensland) for anti-glycine, L. Reichardt (University of California San Francisco) and K. Nave (Max Planck Institute, Göttingen) for Neurod6cre mice, T. Misgeld and J. Lichtman (Harvard University) for MP mice, R. Born and V. Berezovskii (Harvard University) for macaque retinal tissue and X. Duan for advice and assistance with the retrovirus. J.N.K. was supported by a Life Sciences Research Foundation postdoctoral fellowship. This work was supported by a grant from the US National Institutes of Health to J.R.S. and by Collaborative Innovation Award number 43667 from the Howard Hughes Medical Institute.

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J.N.K., P.E.V. and J.R.S. conceived experiments and wrote the manuscript. J.N.K., P.E.V. and M.W.C. performed experiments.

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Correspondence to Joshua R Sanes.

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The authors declare no competing financial interests.

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Kay, J., Voinescu, P., Chu, M. et al. Neurod6 expression defines new retinal amacrine cell subtypes and regulates their fate. Nat Neurosci 14, 965–972 (2011). https://doi.org/10.1038/nn.2859

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