Abstract
Notch signaling is essential for proper lens development, however the specific requirements of individual Notch receptors have not been investigated. Here we report the lens phenotypes of Notch2 conditionally mutant mice, which exhibited severe microphthalmia, reduced pupillary openings, disrupted fiber cell morphology, eventual loss of the anterior epithelium, fiber cell dysgenesis, denucleation defects, and cataracts. Notch2 mutants also had persistent lens stalks as early as E11.5, and aberrant DNA synthesis in the fiber cell compartment by E14.5. Gene expression analyses showed that upon loss of Notch2, there were elevated levels of the cell cycle regulators Cdkn1a (p21Cip1), Ccnd2 (CyclinD2), and Trp63 (p63) that negatively regulates Wnt signaling, plus down-regulation of Cdh1 (E-Cadherin). Removal of Notch2 also resulted in an increased proportion of fiber cells, as was found in Rbpj and Jag1 conditional mutant lenses. However, Notch2 is not required for AEL proliferation, suggesting that a different receptor regulates this process. We found that Notch2 normally blocks lens progenitor cell death. Overall, we conclude that Notch2-mediated signaling regulates lens morphogenesis, apoptosis, cell cycle withdrawal, and secondary fiber cell differentiation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 219-229 |
| Number of pages | 11 |
| Journal | Developmental Biology |
| Volume | 362 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 15 2012 |
| Externally published | Yes |
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Keywords
- Jag1
- Lens development
- Lens fiber cell differentiation
- Notch2
- P21Cip1
ASJC Scopus subject areas
- Developmental Biology
- Cell Biology
- Molecular Biology
Cite this
Conditional ablation of the Notch2 receptor in the ocular lens. / Saravanamuthu, Senthil S.; Le, Tien T.; Gao, Chun Y.; Cojocaru, Radu I.; Pandiyan, Pushpa; Liu, Chunqiao; Zhang, Jun; Zelenka, Peggy S.; Brown, Nadean L.
In: Developmental Biology, Vol. 362, No. 2, 15.02.2012, p. 219-229.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Conditional ablation of the Notch2 receptor in the ocular lens
AU - Saravanamuthu, Senthil S.
AU - Le, Tien T.
AU - Gao, Chun Y.
AU - Cojocaru, Radu I.
AU - Pandiyan, Pushpa
AU - Liu, Chunqiao
AU - Zhang, Jun
AU - Zelenka, Peggy S.
AU - Brown, Nadean L
PY - 2012/2/15
Y1 - 2012/2/15
N2 - Notch signaling is essential for proper lens development, however the specific requirements of individual Notch receptors have not been investigated. Here we report the lens phenotypes of Notch2 conditionally mutant mice, which exhibited severe microphthalmia, reduced pupillary openings, disrupted fiber cell morphology, eventual loss of the anterior epithelium, fiber cell dysgenesis, denucleation defects, and cataracts. Notch2 mutants also had persistent lens stalks as early as E11.5, and aberrant DNA synthesis in the fiber cell compartment by E14.5. Gene expression analyses showed that upon loss of Notch2, there were elevated levels of the cell cycle regulators Cdkn1a (p21Cip1), Ccnd2 (CyclinD2), and Trp63 (p63) that negatively regulates Wnt signaling, plus down-regulation of Cdh1 (E-Cadherin). Removal of Notch2 also resulted in an increased proportion of fiber cells, as was found in Rbpj and Jag1 conditional mutant lenses. However, Notch2 is not required for AEL proliferation, suggesting that a different receptor regulates this process. We found that Notch2 normally blocks lens progenitor cell death. Overall, we conclude that Notch2-mediated signaling regulates lens morphogenesis, apoptosis, cell cycle withdrawal, and secondary fiber cell differentiation.
AB - Notch signaling is essential for proper lens development, however the specific requirements of individual Notch receptors have not been investigated. Here we report the lens phenotypes of Notch2 conditionally mutant mice, which exhibited severe microphthalmia, reduced pupillary openings, disrupted fiber cell morphology, eventual loss of the anterior epithelium, fiber cell dysgenesis, denucleation defects, and cataracts. Notch2 mutants also had persistent lens stalks as early as E11.5, and aberrant DNA synthesis in the fiber cell compartment by E14.5. Gene expression analyses showed that upon loss of Notch2, there were elevated levels of the cell cycle regulators Cdkn1a (p21Cip1), Ccnd2 (CyclinD2), and Trp63 (p63) that negatively regulates Wnt signaling, plus down-regulation of Cdh1 (E-Cadherin). Removal of Notch2 also resulted in an increased proportion of fiber cells, as was found in Rbpj and Jag1 conditional mutant lenses. However, Notch2 is not required for AEL proliferation, suggesting that a different receptor regulates this process. We found that Notch2 normally blocks lens progenitor cell death. Overall, we conclude that Notch2-mediated signaling regulates lens morphogenesis, apoptosis, cell cycle withdrawal, and secondary fiber cell differentiation.
KW - Jag1
KW - Lens development
KW - Lens fiber cell differentiation
KW - Notch2
KW - P21Cip1
UR - http://www.scopus.com/inward/record.url?scp=84856089113&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856089113&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2011.11.011
DO - 10.1016/j.ydbio.2011.11.011
M3 - Article
VL - 362
SP - 219
EP - 229
JO - Developmental Biology
JF - Developmental Biology
SN - 0012-1606
IS - 2
ER -