May 2007
Volume 48, Issue 13
ARVO Annual Meeting Abstract  |   May 2007
Non-Cell Autonomous Roles for AP-2 in RPE Specification
Author Affiliations & Notes
  • E. A. Bassett
    Pathology/Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
  • T. Williams
    Depts. of CFB and CDB, University of Colorado, Denver, Colorado
  • J. A. West-Mays
    Pathology/Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
  • Footnotes
    Commercial Relationships E.A. Bassett, None; T. Williams, None; J.A. West-Mays, None.
  • Footnotes
    Support NIH EY11910 (JWM); RPB (JWM); NIH DE-12728 (TW)
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 5692. doi:
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      E. A. Bassett, T. Williams, J. A. West-Mays; Non-Cell Autonomous Roles for AP-2 in RPE Specification. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5692.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose:: We previously showed that transcription factor AP-2α has cell autonomous roles in lens and cornea development. AP-2α is also expressed in the developing neural retina (NR) and AP-2α null mice exhibit optic cup defects, including duplication of the NR in place of retinal pigmented epithelium (RPE). This defect was not observed when AP-2α was conditionally deleted in the developing retina, suggesting that it may be caused by failure to receive the correct signals from other ocular or extraocular tissues. We have therefore used different AP-2 mutant mouse models to further investigate its role in RPE specification.

Methods:: The Cre-loxP system was used to generate ‘NCC-AP-2α’ and ‘Le-AP-2α’ mutants with AP-2α conditionally deleted from neural crest cells or the lens placode, respectively. Mice heterozygous for AP-2α or AP-2ß were used to generate AP-2α-/- and AP-2ß-/- nullmutants, and ‘Le-AP-2α/AP-2ß-/- mutants (Le-AP-2α micebred onto the AP-2ß null background). The mutant models were examined using histology and immunofluorescence.

Results:: NCC-AP-2α mutants did not exhibit observable RPE defects. As previously reported, the retinas of both Le-AP-2α and AP-2ß null mutants developed normally; however Le-AP-2α/AP-2ß-/- mice showed replacement of RPE by NR-like tissue in the peripheral optic cup, typically in the ventral region. At birth, this NR-like tissue was characterized by expression of Pax6 and indicators of NR differentiation (Brn3b and calretinin), and absent expression the RPE marker Mitf. The duplicated NR in AP-2α null mice was further examined, and shown to express inner NR markers on its outer surface, suggestive of the inverted NR reported during transdifferentiation of the RPE in the chick. Both the AP-2α null and Le-AP-2α/AP-2ß-/- mice exhibited a mispositioning of the optic cup. Given that inductive signals from the surface ectoderm and periocular mesenchyme are crucial for RPE patterning, this mispositioning may have affected the optic cup’s exposure to signals that normally influence RPE specification. In the Le-AP-2α/AP-2ß-/- mutants, the RPE defect may also be attributed to the combination of loss of AP-2α from the surface ectoderm and loss of AP-2ß from the periocular mesenchyme.

Conclusions:: Examination of the different AP-2 mutant models showed that Le-AP-2α/AP-2ß-/- mice exhibited defects in RPE specification comparable to those of AP-2α null mice. Continued characterization of these mutants will be useful for further discerning the signals required for RPE patterning, including the non-cell autonomous roles for AP-2 in RPE specification.

Keywords: retinal development • retinal pigment epithelium • transgenics/knock-outs 

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