The basic concept underlying this application is that mammalian eye development is specified by a number of genes which can be identified and cloned.
The specific aim of the project is to characterize a set of mutations affecting one of these genes, known as Small eyes (Sey), located in the central region of mouse chromosome 2 close to the b-2-microglobulin (b-2-m) locus. This set will include both spontaneous mutants, and mutants induced by radiation (likely to be deletions), or by chemicals (likely to involve single base changes). Both classes will be mapped with respect to (a) the b-2-m locus, and (b) anonymous DNA probes isolated for the specific purpose from human cells transfected with mouse chromosomes and selected for expression of mouse b-2-m. The mapping will be carried out by a combination of classical genetics and Southern analysis making use of restriction fragment length polymorphisms between genes in M.m. domesticus and M. spretus. This will establish a firm base from which to embark upon cloning the Sey gene by chromsome walking, and will provide a valuable genetic resource for studies on the b-2-m region of chromosome 2. Homozygous Sey mutants fail to show lens induction at around 10 days post coitum. The availability of cloned probes closely linked to Sey will allow the unambiguous identification of Sey/Sey embryos at earlier stages of development than at present. Morphological analysis of these embryos will enhance our understanding of the primary defect caused by the Sey mutation. Information gained about the genetics of eye development in the mouse is likely to be applicable to normal and abnormal human eye development. These is considerable evidence that the chromosomal order of groups of genes is conserved between mouse and human. This local synteny makes it probable that the genetic analysis of the Sey region in the mouse will be directly relevant to the human genome. The basic mechanisms of embryonic eye induction are also likely to be highly conserved between mammalian species.
| Dickinson, M E; Kobrin, M S; Silan, C M et al. (1990) Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutant loci. Genomics 6:505-20 |
| Matrisian, L M; Hogan, B L (1990) Growth factor-regulated proteases and extracellular matrix remodeling during mammalian development. Curr Top Dev Biol 24:219-59 |
| Woychik, R P; Generoso, W M; Russell, L B et al. (1990) Molecular and genetic characterization of a radiation-induced structural rearrangement in mouse chromosome 2 causing mutations at the limb deformity and agouti loci. Proc Natl Acad Sci U S A 87:2588-92 |
| Stubbs, L; Huxley, C; Hogan, B et al. (1990) The HOX-5 and surfeit gene clusters are linked in the proximal portion of mouse chromosome 2. Genomics 6:645-50 |
