Alterations in signaling via components of two other pathways shown to be subject to regulation by Ski has also been found to result in persistence of the fetal vasculature: TGFβ/BMP signaling, and retinoic acid (RA) signaling. Both knockout mice lacking
Tgfβ2, and heterozygotes carrying a targeted
Bmp4 allele, have been reported to have excessive vitreous vasculature, and a Peters-like anomaly or anterior segment dysgenesis, respectively.
14 51 However, Ski has been reported to act as a corepressor of both TGFβ and BMP signaling,
23 24 25 26 and so loss of function of Ski would be predicted to result in a net gain of function of TGFβ/BMP signaling. Therefore, this pathway may not be involved in the ocular abnormalities described in
Ski −/− mice. The case for a potential effect on RA signaling is stronger, since both gain and loss of function of RA signaling can induce PHPV. Compound null mutants lacking several combinations of two of the RA receptors were found to have ocular abnormalities that included microphthalmia, retinal coloboma, corneal and eyelid abnormalities, anterior segment dysgenesis, and lens agenesis with low penetrance.
7 8 Although these represent significant overlaps with the
Ski-null ocular phenotype, the expected outcome of a loss of Ski corepression
28 would again be a gain-of-function abnormality. In this case, exposure to excessive RA around midgestation, between E7.5 and E11.5, results in PHPV, microphthalmia, treinal coloboma, and a Peters-like anomaly involving lack of separation between the corneal and lens epithelia.
6 Therefore, the
Ski-null mutation could most likely affect either RA signaling, or p53-dependent gene expression, or both.