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Retinoic acid receptor alpha and the eye

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G. Zhou1*, R.C. Strom1, V. Giguere2, and R.W. Williams1

1Center for Neuroscience, University of Tennessee, Memphis, TN 38163; 2Molecular Oncology Group, Royal Victoria Hospital, McGill University, Montreal, Canada

We have mapped a locus (Nnc1) that modulates total production of retinal ganglion cells (RGCs) in mice (Williams et al., 1998, JN 18:138). Nnc1 maps to a 3 cM interval on chromosome 11 between Hoxb and Krt1. The alpha retinoic acid receptor gene (Rara) also maps in this interval. Given its expression in the inner nuclear layer of the developing eye, Rara is an excellent candidate gene. Here we exploit knockout mice in which the a1 isoform of Rara has been inactivated to test roles of this receptor in eye development and to test its viability as a candidate for Nnc1. We have also studied effects of inactivating all isoforms of the beta receptor (Rarb) on eye development. Eye weights of Rara and Rarb genotypes (+/+, +/-, and -/-) differ by at most 5% (F = 3.62, p = 0.04, df 64 for Rara cases) with a slight reduction in +/- and -/- animals. Lens weight and retinal area are also reduced slightly [areas: 19.9 mm2 (+/+), 19.6 mm2 (+/-), and 19.1 mm2 (-/-); F=3.61, p=0.04, df 24]. Of most importance, the RGC population of adults is completely unaffected by knocking out Rara. Cell counts are 63,000 ± 2,000 (+/+), 64,000 ± 2,300 (+/-), and 62,500 ± 1,200 (-/-) (F = 0.19 p = 0.8, df 27). It is therefore unlikely that Nnc1 is the Rara gene. In contrast, Rarb, a gene that maps to Chr 14 and which is not a candidate for Nnc1, has a very significant effect on RGC number: 64,600 ± 3,300 SE (+/+), 54,000 ± 2,600 (-/-) (t = 2.5 p= 0.037, df 8). [Supported by NIH EY6627 to RW and NCI Canada to VG.]

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