Conditional ablation of the Notch2 receptor in the ocular lens

Senthil S. Saravanamuthu, Tien T. Le, Chun Y. Gao, Radu I. Cojocaru, Pushpa Pandiyan, Chunqiao Liu, Jun Zhang, Peggy S. Zelenka, Nadean L Brown

Research output: Contribution to journalArticle

30 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)219-229
Number of pages11
JournalDevelopmental Biology
Volume362
Issue number2
DOIs
StatePublished - Feb 15 2012
Externally publishedYes

Fingerprint

Notch2 Receptor
Crystalline Lens
Lenses
Cell Cycle
Notch Receptors
Microphthalmos
Cadherins
Morphogenesis
Cataract
Cell Differentiation
Cell Death
Stem Cells
Down-Regulation
Epithelium
Apoptosis
Phenotype
Gene Expression
DNA

Keywords

  • Jag1
  • Lens development
  • Lens fiber cell differentiation
  • Notch2
  • P21Cip1

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology
  • Molecular Biology

Cite this

Saravanamuthu, S. S., Le, T. T., Gao, C. Y., Cojocaru, R. I., Pandiyan, P., Liu, C., ... Brown, N. L. (2012). Conditional ablation of the Notch2 receptor in the ocular lens. Developmental Biology, 362(2), 219-229. https://doi.org/10.1016/j.ydbio.2011.11.011

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 journalArticle

Saravanamuthu, SS, Le, TT, Gao, CY, Cojocaru, RI, Pandiyan, P, Liu, C, Zhang, J, Zelenka, PS & Brown, NL 2012, 'Conditional ablation of the Notch2 receptor in the ocular lens', Developmental Biology, vol. 362, no. 2, pp. 219-229. https://doi.org/10.1016/j.ydbio.2011.11.011
Saravanamuthu SS, Le TT, Gao CY, Cojocaru RI, Pandiyan P, Liu C et al. Conditional ablation of the Notch2 receptor in the ocular lens. Developmental Biology. 2012 Feb 15;362(2):219-229. https://doi.org/10.1016/j.ydbio.2011.11.011
Saravanamuthu, Senthil S. ; Le, Tien T. ; Gao, Chun Y. ; Cojocaru, Radu I. ; Pandiyan, Pushpa ; Liu, Chunqiao ; Zhang, Jun ; Zelenka, Peggy S. ; Brown, Nadean L. / Conditional ablation of the Notch2 receptor in the ocular lens. In: Developmental Biology. 2012 ; Vol. 362, No. 2. pp. 219-229.
@article{165455879b9a4f0bab76522af2c4b9bb,
title = "Conditional ablation of the Notch2 receptor in the ocular lens",
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.",
keywords = "Jag1, Lens development, Lens fiber cell differentiation, Notch2, P21Cip1",
author = "Saravanamuthu, {Senthil S.} and Le, {Tien T.} and Gao, {Chun Y.} and Cojocaru, {Radu I.} and Pushpa Pandiyan and Chunqiao Liu and Jun Zhang and Zelenka, {Peggy S.} and Brown, {Nadean L}",
year = "2012",
month = "2",
day = "15",
doi = "10.1016/j.ydbio.2011.11.011",
language = "English (US)",
volume = "362",
pages = "219--229",
journal = "Developmental Biology",
issn = "0012-1606",
publisher = "Academic Press Inc.",
number = "2",

}

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 -