Genetic rescue of cell number in a mouse model of microphthalmia: interactions between Chx10 and G1-phase cell cycle regulators
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Eric S Green1, Jennifer L Stubbs, Edward M Levine
1Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT 84132, USA.
Abstract:
Insufficient cell number is a primary cause of failed retinal development in the Chx10 mutant mouse. To determine if Chx10 regulates cell number by antagonizing p27(Kip1) activity, we generated Chx10, p27(Kip1) double null mice. The severe hypocellular defect in Chx10 single null mice is alleviated in the double null, and while Chx10-null retinas lack lamination, double null retinas have near normal lamination. Bipolar cells are absent in the double null retina, a defect that is attributable to a requirement for Chx10 that is independent of p27(Kip1). We find that p27(Kip1) is abnormally present in progenitors of Chx10-null retinas, and that its ectopic localization is responsible for a significant amount of the proliferation defect in this microphthalmia model system. mRNA and protein expression patterns in these mice and in cyclin D1-null mice suggest that Chx10 influences p27(Kip1) at a post-transcriptional level, through a mechanism that is largely dependent on cyclin D1. This is the first report of rescue of retinal proliferation in a microphthalmia model by deletion of a cell cycle regulatory gene.
Insights
Chx10, a gene crucial for retinal development, regulates cell number by antagonizing p27(Kip1). Deleting both genes rescues retinal cell proliferation in a microphthalmia model.
Area of Science:
- Developmental biology
- Genetics
- Ophthalmology
Background:
- Insufficient cell number is a primary cause of failed retinal development in Chx10 mutant mice.
- Chx10's role in regulating cell number and its relationship with p27(Kip1) activity remain unclear.
Purpose of the Study:
- To investigate whether Chx10 antagonizes p27(Kip1) activity to regulate cell number.
- To explore the underlying mechanisms of Chx10's function in retinal development.
Main Methods:
- Generation of Chx10 and p27(Kip1) double null mice.
- Analysis of retinal development, cell number, lamination, and cell-specific markers.
- Examination of mRNA and protein expression patterns, including in cyclin D1-null mice.
Main Results:
- The hypocellular defect in Chx10 null retinas was alleviated in double null mice, with near-normal lamination.
- Bipolar cell absence in double null retinas indicates a p27(Kip1)-independent role for Chx10.
- Abnormal p27(Kip1) localization in Chx10-null progenitors contributed significantly to proliferation defects.
- Chx10 influences p27(Kip1) post-transcriptionally, largely dependent on cyclin D1.
Conclusions:
- Deletion of p27(Kip1) rescues retinal cell proliferation in a Chx10-dependent microphthalmia model.
- Chx10 antagonizes p27(Kip1) activity, regulating progenitor proliferation and retinal lamination.
- This study reveals a novel mechanism involving Chx10, p27(Kip1), and cyclin D1 in retinal development.
