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12 02, 2022;11

Lhx2 is a progenitor-intrinsic modulator of Sonic Hedgehog signaling during early retinal neurogenesis.

Xiaodong Li, Patrick J Gordon, John A Gaynes, Alexandra W Fuller, Randy Ringuette, Clayton P Santiago, Valerie Wallace, Seth Blackshaw, Pulin Li, Edward M Levine
Author Information
  1. Xiaodong Li: Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, United States. ORCID
  2. Patrick J Gordon: John A. Moran Eye Center, University of Utah, Salt Lake City, United States.
  3. John A Gaynes: John A. Moran Eye Center, University of Utah, Salt Lake City, United States.
  4. Alexandra W Fuller: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States.
  5. Randy Ringuette: Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
  6. Clayton P Santiago: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States. ORCID
  7. Valerie Wallace: Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada. ORCID
  8. Seth Blackshaw: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States. ORCID
  9. Pulin Li: Whitehead Institute of Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
  10. Edward M Levine: Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, United States. ORCID
PMID: 36459481 DOI: 10.7554/eLife.78342

Abstract

An important question in organogenesis is how tissue-specific transcription factors interact with signaling pathways. In some cases, transcription factors define the context for how signaling pathways elicit tissue- or cell-specific responses, and in others, they influence signaling through transcriptional regulation of signaling components or accessory factors. We previously showed that during optic vesicle patterning, the Lim-homeodomain transcription factor Lhx2 has a contextual role by linking the Sonic Hedgehog (Shh) pathway to downstream targets without regulating the pathway itself. Here, we show that during early retinal neurogenesis in mice, Lhx2 is a multilevel regulator of Shh signaling. Specifically, Lhx2 acts cell autonomously to control the expression of pathway genes required for efficient activation and maintenance of signaling in retinal progenitor cells. The Shh co-receptors Cdon and Gas1 are candidate direct targets of Lhx2 that mediate pathway activation, whereas Lhx2 directly or indirectly promotes the expression of other pathway components important for activation and sustained signaling. We also provide genetic evidence suggesting that Lhx2 has a contextual role by linking the Shh pathway to downstream targets. Through these interactions, Lhx2 establishes the competence for Shh signaling in retinal progenitors and the context for the pathway to promote early retinal neurogenesis. The temporally distinct interactions between Lhx2 and the Shh pathway in retinal development illustrate how transcription factors and signaling pathways adapt to meet stage-dependent requirements of tissue formation.

Keywords

Lhx2 Sonic Hedgehog development developmental biology genetics genomics mouse retina signaling

Associated Data

GEO | GSE172457; GSE99818

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Grants

  1. R00 HD087532/NICHD NIH HHS
  2. R01 EY013760/NEI NIH HHS
  3. R01 AG020560/NIA NIH HHS
  4. R01 EY031685/NEI NIH HHS
  5. P30 EY014800/NEI NIH HHS
  6. P30 EY008126/NEI NIH HHS
  7. DP2 HD108777/NICHD NIH HHS

MeSH Term

Mice
Animals
Hedgehog Proteins
Neurogenesis
Retina
Signal Transduction
Transcription Factors
LIM-Homeodomain Proteins

Chemicals

Hedgehog Proteins
Transcription Factors
Lhx2 protein, mouse
LIM-Homeodomain Proteins
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

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