Nephron-deficient Fvb mice develop rapidly progressive renal failure and heavy albuminuria involving excess glomerular GLUT1 and VEGF.

Reduced nephron numbers may predispose to renal failure. We hypothesized that glucose transporters (GLUTs) may contribute to progression of the renal disease, as GLUTs have been implicated in diabetic glomerulosclerosis and hypertensive renal disease with mesangial cell (MC) stretch. The Os (oligosyndactyly) allele that typically reduces nephron number by approximately 50%, was repeatedly backcrossed from ROP (Ra/+ (ragged), Os/+ (oligosyndactyly), and Pt/+ (pintail)) Os/+ mice more than six times into the Fvb mouse background to obtain Os/+ and +/+ mice with the Fvb background for study.

Igf2r improves the survival and transmission ratio of Igf2 transgenic mice.

Mammals with excess insulin-like growth factor 2 (IGFII) during embryogenesis have developmental defects that can lead to perinatal lethality. In adults, higher levels of IGFII increase the risk of cancer and may accelerate the development of atherosclerosis. IGFII can be increased as a consequence of genetic abnormalities and polymorphisms, and through epigenetic mechanisms.

Delayed onset of Igf2-induced mammary tumors in Igf2r transgenic mice.

The insulin-like growth factor-II (IGF-II) receptor (IGF2R) regulates the level or activity of numerous proteins, including factors that control growth and differentiation. Frequent loss or inactivation of this receptor in a diverse group of tumors indicates that it may act as a tumor suppressor, but it is not known which functions of this receptor are selected against in the tumors. Lysosomal targeting and degradation of the growth-promoting IGF-II has been proposed as a mechanism for the tumor suppressor effects of IGF2R.

Oligosyndactylism mice have an inversion of chromosome 8.

The radiation-induced mutation Oligosyndactylism (Os) is associated with limb and kidney defects in heterozygotes and with mitotic arrest and embryonic lethality in homozygotes. We reported that the cell cycle block in Os and in the 94-A/K transgene-induced mutations is due to disruption of the Anapc10 (Apc10/Doc1) gene. To understand the genetic basis of the limb and kidney abnormalities in Os mice we characterized the structural changes of chromosome 8 associated with this mutation.

Transgene instability in mice injected with an in vitro methylated Igf2 gene.

Foreign DNA injected into mouse embryos integrates into the host chromosomes and is usually transmitted stably to the progeny. Rare cases of transgene instability have been described, and these can help our understanding of the rules that govern the organization and stability of endogenous DNA. We have observed unusual inheritance in three transgenic lines produced with a partially in vitro methylated Igf2 construct.

Disruption of Apc10/Doc1 in three alleles of oligosyndactylism.

Oligosyndactylism (Os) is a radiation-induced mouse mutation associated with recessive lethality and a dominant effect on limb and kidney development. The lethal effect of the mutation is due to a cell-autonomous block in the transition from metaphase to anaphase. We have previously characterized two transgene-induced mutations, 94-A and 94-K, which are allelic with Os.

The undermethylated state of a CpG island region in igf2 transgenes is dependent on the H19 enhancers.

CpG islands are GC-rich regions located in the promoter regions of housekeeping genes and many tissue-specific genes. While most CpG islands are normally unmethylated, island methylation can occur and is associated with silencing of the corresponding gene. Experiments with transgenic mice and DNA transfection in pluripotential embryonic cells have led to the conclusion that the information required for protecting the islands from methylation is contained within the CpG islands themselves and have identified Sp1 binding sites as an important element in establishing and/or maintaining the methylation-free state of CpG islands.

Metastasizing mammary carcinomas in H19 enhancers-Igf2 transgenic mice.

The insulin-like growth factor II is mitogenic for a number of cell types and can inhibit apoptosis. The frequent expression of this gene in human and experimental animal tumors indicates that insulin-like growth factor-2 may play an important role in tumor development. It has also been hypothesized that overexpression of this growth factor may be responsible for the increased incidence of childhood tumors in patients with Beckwith-Wiedemann syndrome.

A transgene-induced mitotic arrest mutation in the mouse allelic with Oligosyndactylism.

Oligosyndactylism (Os) is a radiation-induced mutation on mouse chromosome 8 associated with early postimplantation lethality in homozygotes and abnormal development of the limbs and kidneys in heterozygotes. The recessive lethal effect of Os is due to a mitotic block of the embryonic cells that becomes apparent at the blastocyst stage, but it is not known if the heterozygous effect of Os is due to haploinsufficiency of the gene responsible for the mitotic arrest, or is due to mutation(s) of other gene(s). We have recently described a transgene-induced recessive mutation, 94-A/K, that results in early postimplantation death of the embryos, and we have mapped this mutation to the same region of chromosome 8 where Os has been assigned.

A postimplantation lethal mutation induced by transgene insertion on mouse chromosome 8.

We have produced three lines of transgenic mice that contain additional copies of the mouse phosphoglycerate kinase 1 (Pgk1) gene. Two of these lines, 94-A and 94-K, which are descendants of a common founder, did not produce liveborn progeny carrying two copies of these transgenes (i.e.

Chromosomal location and some structural features of human clathrin light-chain genes (CLTA and CLTB).

Two human clathrin light-chain genes have been defined. The gene (CLTA) encoding the LCa light chain maps to the long arm of chromosome 12 at 12q23-q24 and that encoding the LCb light chain (CLTB) maps to the long arm of chromosome 4 at 4q2-q3. Isolation and characterization of partial genomic clones encoding human LCa and LCb reveal the neuron-specific insertions of the LCa and LCb proteins to be encoded by discrete exons, thus proving that clathrin light chains undergo alternate mRNA splicing to generate tissue-specific protein isoforms.

Mosaic expression of an Hprt transgene integrated in a region of Y heterochromatin.

The sensitivity of small transgenes to position effects on their expression suggests that they could serve as indicators of the chromatin properties at their integration site. In particular, they might be expected to provide information on the functional properties of mammalian heterochromatin. We have produced a transgenic line that carries a mouse Hprt minigene on the Y chromosome.

Glial fibrillary acid protein, an astrocytic-specific marker, maps to human chromosome 17.

The murine glial fibrillary acid protein (GFAP) gene is located on chromosome 11 in close proximity to the genes encoding transforming protein p53 (Trp53) and myeloperoxidase (Mpo). Both Trp53 and Mpo have been mapped to human chromosome 17, but the chromosomal assignment of human GFAP has not been previously determined. In this report, we have amplified a cDNA fragment encoding a portion of GFAP from human brain and have used this probe to screen a mouse x human somatic cell hybrid panel.

Timing of paternal Pgk-1 expression in embryos of transgenic mice.

In mouse development, the paternal allele of the X-linked gene Pgk-1 initiates expression on day 6, two days later than the maternal allele, which is activated on day 4. The different timing of expression of the maternal and paternal alleles may be determined by (i) imprinting of the chromosome region in which the gene resides, but not aimed specifically at the Pgk-1 gene; (ii) gene specific imprinting, acting on Pgk-1 irrespective of the chromosomal localization of the gene; (iii) an interplay between embryo cell differentiation, timing of X-inactivation and Pgk-1 expression, without the involvement of imprinting at the Pgk-1 locus itself (Fundele R., Illmensee, K.

Mouse Hox-3.4: homeobox sequence and embryonic expression patterns compared with other members of the Hox gene network.

A putative mouse homeobox gene (Hox-3.4) was previously identified 4kb downstream of the Hox-3.3 (Hox-6.

The gene encoding peripheral myelin protein zero is located on mouse chromosome 1.

We have used somatic cell hybrids to map the gene encoding protein zero (P0), the major structural protein of peripheral myelin. Analysis of Southern blots of DNA obtained from these hybrids allows us to unambiguously assign the P0 gene to mouse chromosome 1. This observation indicates that mutations in the P0 gene do not account for Trembler, a chromosome 11 mutation that specifically affects myelination in the peripheral nervous system.

Association of foreign DNA sequence with male sterility and translocation in a line of transgenic mice.

We have analyzed a line of transgenic mice derived from injection of a cloned human interferon cDNA. This line manifests total male sterility of males carrying the human sequence, while male littermates not harboring the foreign DNA are fertile. All females are fertile.

Chromosome assignment of the murine Hox-4.1 gene.

The murine homebox gene 4.1 was assigned to chromosome 2 by Southern analysis of somatic cell hybrids and by in situ hybridization. This assignment and the report of Featherstone et al.

Localization of the cryptdin locus on mouse chromosome 8.

Cryptdin is a defensin-related peptide, and its mRNA accumulates to high abundance in epithelial cells of intestinal crypts beginning in the second week of postnatal development. The cryptdin (Defcr) locus was assigned to mouse chromosome 8 by Southern blotting of DNAs from mouse/hamster somatic hybrid cell lines. Analysis of somatic hybrid DNAs for mouse-specific restriction fragments showed zero discordance and perfect concordance with chromosome 8.

Interferons as gene activators: a cluster of six interferon-activatable genes is linked to the erythroid alpha-spectrin locus on murine chromosome 1.

Several interferon-activatable murine genes were mapped to murine chromosomes by hybridizing cDNA probes to Southern blots of genomic DNA samples from a panel of mouse-hamster somatic cell hybrid lines. The 12 gene is located on chromosome 12 and it specifies a 3.6-kb mRNA.

Isolation and regional localization of the murine homeobox-containing gene Hox-3.3 to mouse chromosome region 15E.

A murine homeobox-containing cDNA clone has been isolated from an adult spinal cord library. Using in situ hybridization and somatic cell genetics techniques, the newly isolated homeobox gene has been mapped to mouse chromosome region 15E. Because of its chromosomal location, we called this gene locus Hox-3.

D10S20, a previously unmapped RFLP (OS-3), is located on 10q near D10S4.

The locus recognized by the probe OS-3 is assigned to chromosome 10 both by Southern blot analysis of a panel of somatic cell hybrid DNAs and by genetic linkage to markers already assigned to chromosome 10. In Caucasians this probe recognizes a three-allele TaqI RFLP as well as two-allele BanII and RsaI RFLPs which are both in strong linkage disequilibrium with each other and with the TaqI RFLP. The D10S20 locus defined by this probe maps 5.

Chromosomal mapping of the prolactin/growth hormone gene family in the mouse.

The chromosomal assignments of genes in the PRL/GH family in the mouse have been determine in mouse-hamster hybrid cell lines. Mouse GH (mGH) appears to be encoded by a single copy gene located on chromosome 11 and is part of a highly conserved region between mouse chromosome 11 and human chromosome 17. All of the other genes in this hormone family, including those encoding mPRL, mouse placental lactogens I and II, and mouse proliferin and proliferin-related protein, map to chromosome 13.

The gene for T11 (CD2) maps to chromosome 1 in humans and to chromosome 3 in mice.

The chromosomal locations of the human and murine T11 (CD2) gene have been determined. Using recently cloned cDNA to probe Southern blots of mouse X human and Chinese hamster X mouse somatic cell hybrids, we have localized the human T11 gene to chromosome 1 and the murine T11 gene to chromosome 3. Based on previously determined blocks of homology between human chromosome 1 and mouse chromosome 3, it is suggested that the human T11 gene may lie on the short arm of chromosome 1 proximal to p221.