Thomas H. Roderick

Ocular retardation mouse caused by Chx10 homeobox null allele: Impaired retinal progenitor proliferation and bipolar cell differentiation

Ocular retardation (or) is a murine eye mutation causing microphthalmia, a thin hypocellular retina and optic nerve aplasia. Here we show that mice carrying the orJ allele have a premature stop codon in the homeobox of the Chx1O gene, a gene expressed at high levels in uncommitted retinal progenitor cells and mature bipolar cells. No CHX10 protein was detectable in the retinal neuroepithelium of orJ homozygotes. The loss of CHX10 leads both to reduced proliferation of retinal progenitors and to a specific absence of differentiated bipolar cells. Other major retinal cell types were present and correctly positioned in the mutant retina, although rod outer segments were short and retinal lamination was incomplete. These results indicate that Chx10 is an essential component in the network of genes required for the development of the mammalian eye, with profound effects on retinal progenitor proliferation and bipolar cell specification or differentiation

Interacting loci cause severe iris atrophy and glaucoma in DBA/2J mice.

Glaucomas are a major cause of blindness. Visual loss typically involves retinal ganglion cell death and optic nerve atrophy subsequent to a pathologic elevation of intraocular pressure (IOP). Some human glaucomas are associated with anterior segment abnormalities such as pigment dispersion syndrome (PDS) and iris atrophy with associated synechiae. The primary causes of these abnormalities are unknown, and their aetiology is poorly understood. We recently characterized a mouse strain (DBA/2J) that develops glaucoma subsequent to anterior segment changes including pigment dispersion and iris atrophy. Using crosses between mouse strains DBA/2J (D2) and C57BL/6J (B6), we now show there are two chromosomal regions that contribute to the anterior segment changes and glaucoma. Progeny homozygous for the D2 allele of one locus on chromosome 6 (called ipd) develop an iris pigment dispersion phenotype similar to human PDS. ipd resides on a region of mouse chromosome 6 with conserved synteny to a region of human chromosome 7q that is associated with human PDS (ref. 4 ). Progeny homozygous for the D2 allele of a different locus on chromosome 4 (called isa) develop an iris stromal atrophy phenotype (ISA). The Tyrp1 gene is a candidate for isa and likely causes ISA via a mechanism involving pigment production. Progeny homozygous for the D2 alleles of both ipd and isa develop an earlier onset and more severe disease involving pigment dispersion and iris stromal atrophy.

Linkage analyses using biochemical variants in mice. III. Linkage relationships of eleven biochemical markers.

The linkage relationships of 11 loci concerned with protein or enzyme variation in the inbred mouse (Mus musculus) have been investigated. By means of a three-point cross, the order of the loci glucosephosphate isomerase (Gpi-1), albino (c), and hemoglobin β-chain in linkage group I has been established as Gpi-c-Hbb. Similarly, the order of the loci autosomal glucose 6-phosphate dehydrogenase (Gpd-1), misty (m), and brown (b) in linkage group VIII has been established as Gpd-m-b. The levulinate dehydratase locus (Lv) in linkage group VIII which shows 5±2% recombination with the brown locus is near the anemia locus (an). The locus for malic dehydrogenase (Mdh-1) shows 10.1±2.9% recombination with the dilute locus and 12.0±6.5% recombination with the luxoid locus. The tentative order of the three loci is d-Mdh-1-lu. Recombination between the isocitric dehydrogenase locus (Id-1) and the leaden locus (ln) is 16.7±5.8% and between Id-1 and the splotch locus (Sp) is 11.0±5.4% in linkage group XIII. The tentative order of the three loci is ln-Sp-Id-1. Recombination between the lactic dehydrogenase regulatory locus (Ldr-1) and the microphthalmia locus (Miwh) in linkage group XI is 28.7±4.4%. Recombination between the phosphoglucomutase locus (Pgm-1) and the W-locus in linkage group XVII is 3.0±1.7%. The esterase-3 locus has not been placed in a linkage group and has been tested against markers on linkage groups I, II, III, IV, V, VI, VIII, XI, XII, XIII, XVI, XVII, XVIII, and XX. In no case was there physical linkage of structural genes whose products participate in related metabolic pathways.

Biochemical polymorphisms in feral and inbred mice (mus musculus).

Examination of the frequencies of several loci controlling isozymes in three geographically distinct feral populations of mice showed the average animal to be heterozygous at 10.3% of his loci. There was no evidence for interaction between loci, nor any evidence for inbreeding in the populations. Thirty-nine inbred strains, including four newly derived ones, were also characterized for their alleles for as many as 16 polymorphic loci. Among these strains, variability is at least as great as in any single feral population, but probably less than that found among all feral populations of the species.

Phosphoglucomutase electrophoretic variants in the mouse

The phosphoglucomutase (PGM) electrophoretic phenotype of the mouse (Mus musculus) consists of several distinct components which can be grouped into two major zones designated PGM-1 and PGM-2. Evidence presented here indicates that each zone is controlled by a single genetic locus denoted Pgm-1 and Pgm-2, respectively. Two variant forms segregated at the Pgm-1 locus. They were codominantly expressed and inherited as alleles at an autosomal locus. The alleles were termed Pgm-1a (fast) and Pgm-1b (slow). These alleles were separately fixed in a number of inbred strains of mice. Preliminary evidence based on wild mouse phenotypes indicates that variant forms also exist for PGM-2 which are inherited as alleles at an autosomal locus. Genetic linkage relationships have not been determined for these loci. PGM-1 variants and PGM-2 were expressed in mouse fibroblasts in vitro.

Evolution of mammalian carbonic anhydrase loci by tandem duplication. Close linkage of car-1 and car-2 to the centromere region of chromosome 3 of the mouse.

Electrophoretic variants of two carbonic anhydrase enzymes, CAR-1 (CA I) and CAR-2 (CA II), have been found in the laboratory mouse, Mus musculus. These two loci are closely linked to each other and are located on chromosome 3 near its centromere. The close linkage of Car-1 and Car-2 supports the hypothesis that the present-day carbonic anhydrase loci are the result of tandem duplication of an earlier carbonic anhydrase locus with subsequent divergence. The red blood cells of mice of the subspecies M. m. casteneus have significantly reduced levels of CAR-1 and CAR-2.

Linkage of isozyme loci in the mouse: Phosphoglucomutase-2 (Pgm-2), mitochondrial NADP malate dehydrogenase (Mod-2), and dipeptidase-1 (Dip-1)

The linkages of the isozyme genes Mod-2, Pgm-2, and Dip-1 have been determined in tests with established linkage group markers among inbred strains of mice. Unique alleles for both Mod-2 and Pgm-2 have been observed in the strain of SM/J. Linkage was determined from backcross progeny of the matings C57BL/6J×(SM/J×C57BL/6J)F1, (SM/J×SWR/J)F1×SM/J, and (SM/J×SWR/J)F1×SJL/J. The gene Mod-2 is on linkage group 1. In a three-point cross of the loci Gpi-1, c, and Mod-2, the c locus was determined to be the middle gene. No double crossovers were observed. Our combined data show the following linkages: Gpi-1 to c, 28.3±3.2%; Gpi-1 to Mod-2, 33.3±3.0%; and c to Mod-2, 4.1±2.8%. The proposed gene order for four markers on LG I is Gpi-1-p-c-Mod-2. The gene Pgm-2 was linked to Gpd-1 (27.0±4.2%) on LGVIII. Two backcrosses segregating for Pgm-2 and b, (SM/J×DBA/2J) F1×DBA/2J and (SM/J×DBA/2J)F1×C57BR/cdJ, showed 9.1±4.3% recombination. The proposed gene order on LG VIII is b-Pgm-2-Gpd-1. The genes Pgm-1 and Pgm-2 are not linked (53.4±4.4%). Linkage of the isozyme genes Dip-1 and Id-1 on LG XIII was observed in backcross progeny of the crosses (SJL/J×C57BL/6J)F1×SJL/J and C57BL/6J×(SM/J×C57BL/6J)F1. The combined recombination was 23.8±2.8%. Two cases are established where genes whose enzyme products share substrate affinities (Pgm-1 and Pgm-2; Mod-1 and Mod-2) are not linked. Our data generally support the conclusion that functionally or metabolically related isozyme genes are not contiguous on mouse linkage groups.

Producing and detecting paracentric chromosomal inversions in mice

Abstract Three feasible methods for finding chromosomal inversions were discussed and recent data obtained from each method were given. The “radiation and anaphase-bridge method” has provided 5 useful paracentric inversions. The first inversion proved useful (1) in locating locus dipeptidase-1 ( Dip -1); ( 2 ) in predicting the location of the centromere in linkage group XVII; and ( 3 ) because of the fortuitous association of marker genes, in providing a balanced lethal system to detect and retain newly induced recessive lethals. Hybrid males of the interfertile subspecies Mus m. molossinus and Mus m. musculus displayed a high frequency of first meiotic anaphase bridges and double bridges, suggesting that the chromosomal arrangements of these subspecies differ by at least two paracentric inversions.

Genetic variation in alkaline phosphatase of the house mouse (Mus musculus) with emphasis on a manganese-requiring isozyme.

AbstractGenetic variation among inbred strains is described for electrophoretic migration of alkaline phosphatase from intestine, kidney, blood plasma, and three isozymes of liver. A manganese-requiring isozyme of liver and kidney unaffected by neuraminidase is described, and the locus controlling variation in this isozyme is designated Akp-1. Data from recombinant inbred strains place the locus on chromosome 1 at a distance of 3.6±2.9 cM from the Mls locus on the side distal to the centromere. Test-cross data show the following gene order and recombination percentages: