Math5 defines the ganglion cell competence state in a subpopulation of retinal progenitor cells exiting the cell cycle

Joseph A. Brzezinski, Lev Prasov, Thomas M Glaser

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

The basic helix-loop-helix (bHLH) transcription factor . Math5 (. Atoh7) is transiently expressed during early retinal histogenesis and is necessary for retinal ganglion cell (RGC) development. Using nucleoside pulse-chase experiments and clonal analysis, we determined that progenitor cells activate . Math5 during or after the terminal division, with progressively later onset as histogenesis proceeds. We have traced the lineage of . Math5+ cells using mouse BAC transgenes that express Cre recombinase under strict regulatory control. Quantitative analysis showed that . Math5+ progenitors express equivalent levels of . Math5 and contribute to every major cell type in the adult retina, but are heavily skewed toward early fates. The Math5. >. Cre transgene labels 3% of cells in adult retina, including 55% of RGCs. Only 11% of . Math5+ progenitors develop into RGCs; the majority become photoreceptors. The fate bias of the . Math5 cohort, inferred from the ratio of cone and rod births, changes over time, in parallel with the remaining neurogenic population. Comparable results were obtained using . Math5 mutant mice, except that ganglion cells were essentially absent, and late fates were overrepresented within the lineage. We identified . Math5-independent RGC precursors in the earliest born (embryonic day 11) retinal cohort, but these precursors require . Math5-expressing cells for differentiation. . Math5 thus acts permissively to establish RGC competence within a subset of progenitors, but is not sufficient for fate specification. It does not autonomously promote or suppress the determination of non-RGC fates. These data are consistent with progressive and temporal restriction models for retinal neurogenesis, in which environmental factors influence the final histotypic choice.

Original languageEnglish (US)
Pages (from-to)395-413
Number of pages19
JournalDevelopmental Biology
Volume365
Issue number2
DOIs
StatePublished - May 15 2012

Fingerprint

Ganglia
Mental Competency
Cell Cycle
Stem Cells
Retinal Ganglion Cells
Transgenes
Retina
Basic Helix-Loop-Helix Transcription Factors
Vertebrate Photoreceptor Cells
Neurogenesis
Nucleosides
Cell Differentiation
Parturition
Population

Keywords

  • Atonal
  • BAC transgenic
  • BHLH
  • Cell fate determination
  • Cre recombinase
  • Expression fate mapping
  • Genetics
  • Lineage
  • Mouse
  • Optic nerve
  • Retina

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology
  • Molecular Biology

Cite this

Math5 defines the ganglion cell competence state in a subpopulation of retinal progenitor cells exiting the cell cycle. / Brzezinski, Joseph A.; Prasov, Lev; Glaser, Thomas M.

In: Developmental Biology, Vol. 365, No. 2, 15.05.2012, p. 395-413.

Research output: Contribution to journalArticle

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abstract = "The basic helix-loop-helix (bHLH) transcription factor . Math5 (. Atoh7) is transiently expressed during early retinal histogenesis and is necessary for retinal ganglion cell (RGC) development. Using nucleoside pulse-chase experiments and clonal analysis, we determined that progenitor cells activate . Math5 during or after the terminal division, with progressively later onset as histogenesis proceeds. We have traced the lineage of . Math5+ cells using mouse BAC transgenes that express Cre recombinase under strict regulatory control. Quantitative analysis showed that . Math5+ progenitors express equivalent levels of . Math5 and contribute to every major cell type in the adult retina, but are heavily skewed toward early fates. The Math5. >. Cre transgene labels 3{\%} of cells in adult retina, including 55{\%} of RGCs. Only 11{\%} of . Math5+ progenitors develop into RGCs; the majority become photoreceptors. The fate bias of the . Math5 cohort, inferred from the ratio of cone and rod births, changes over time, in parallel with the remaining neurogenic population. Comparable results were obtained using . Math5 mutant mice, except that ganglion cells were essentially absent, and late fates were overrepresented within the lineage. We identified . Math5-independent RGC precursors in the earliest born (embryonic day 11) retinal cohort, but these precursors require . Math5-expressing cells for differentiation. . Math5 thus acts permissively to establish RGC competence within a subset of progenitors, but is not sufficient for fate specification. It does not autonomously promote or suppress the determination of non-RGC fates. These data are consistent with progressive and temporal restriction models for retinal neurogenesis, in which environmental factors influence the final histotypic choice.",
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