Michael F. Seldin

Bio: Michael F. Seldin is an academic researcher from University of California, Davis. The author has contributed to research in topics: Gene & Gene mapping. The author has an hindex of 5, co-authored 6 publications receiving 644 citations. Previous affiliations of Michael F. Seldin include University of California, Berkeley & Duke University.

Mapping of six germ-cell-specific genes to mouse chromosomes.

Abstract: compared with 11 days p.c. are: 7 days p.c. 80%, 11 days p.c. 100%, 15 days p.c. 89%, 17 days p.c. 29%. Expression of a 1.95kb signal was also detected in adult lung and testes but not heart, brain, spleen, skeletal muscle, or testes. Discussion: The molecular events involved in conversion of pleuripotent epithelial derivatives into various neural crest derivatives require complex cellular and environmental interactions modulated by lineage-specific transcription factors. One important event in the development of neural crest-derived cells is the transition of epithelial to mesenchymal characteristics during emigration from the neural tube. Slug, a zinc finger protein, is one gene believed to play an important role in this transition [2,3]. Slug is a neurogenic, transcription factor belonging to the Snail family in Drosophila melanogaster. Embryological studies in chick and frog demonstrated that Slug mRNA is expressed in the developing neural crest and in mesodermal cells emerging from the primitive streak [3-5]. Indirect functional analyses with antisense oligonucleotides to the Slug mRNA showed specific and transient developmental failures at the early embryonic stages. These failures resulted in defects in neural tube closure between the midbrain and cervical regions, block of the epithelial-mesenchymal transition in the neural crest, and in the emergence of mesoderm from the primitive streak. These anomalies suggest that SLUG is required for the genetic control of cell activity during early stages of neural tube and neural crest development. Consistent with a role for SLUGH function in mouse embryonic development, our Northern blot analyses demonstrated that Slugh is expressed at 7 days p.c., and the signal intensity decreases subsequent to 11 days p.c. Further experiments with in situ hybridization or immunohistochemistry will be necessary to determine the specific sites of Slug expression during mouse embryogenesis. Identification of known mutations caused by alterations of specific genes can provide essential clues for understanding the normal function of those genes in mammalian development. To determine whether Slugh is a candidate gene for a disease locus, we identified the chromosomal localization of Slugh in the mouse and human genomes. Segregation analysis of a Slugh RFLP in The Jackson Laboratory FI(C57BL/6J x Mus spretus) x Mus spretus (BSS) interspecific backcross panel [1] determined that the mouse Slugh gene is located on the proximal end of Chr 16 and cosegregated with four previously mapped loci: Tbxl (T/omb homologous domain containing gene 1), D16Bir4, D16Hun3, and Gplbb (Fig. 1). An interspecies somatic-cell hybrid (SCH) panel was used to determine the chromosomal localization of SLUGH in the human genome. The mouse Slugh cDNA hybridized to a human-specific 10 kb band in two SCH lanes: one SCH cell line containing only human Chr 8; the other SCH cell line containing three human chromosomes, 4, 8, and 20 (Fig. 2). This result indicated that SLUGH was located on human Chr 8. Only one other gene, a CCAAT/enhancer binding protein, C/EBP-delta (CRP3/CELF), has been localized to this portion of human Chr 8 and mouse Chr 16 ([6], mouse human homology map http://www3.ncbi.nlm.nih. gov/Homology/mousel6.html). Therefore, to confirm and further refine the localization of Slugh in the human genome, we identified a human SLUGH EST and determined its human map location with the Stanford G3 radiation hybrid (RH) mapping panel (http:// shgc.stanford.edu/RH/index.html). Comparison of RH mapping data with previously scored markers determined that SLUGH was closely linked to marker D8S2090 (LOD 15) on human Chr 8 at cM 66-69 (http://www/ncbi.nlm.nih.gov/cgi-bin/SCIENCE96/ loc?WI-8188, h t tp : / /www.ncbi .n lm.nih .gov/cgi -b in /Schuler / clust2html?Homo+sapiens+8760). These data are consistent with and further define a region of conserved linkage between mouse Chr 16 and human Chr 8ql 1. Survey of the biomedical literature did not indicate any genetically linked, mammalian disease loci that would suggest a defect in Slugh. Therefore, additional molecular and embryonic studies of SLUGH function are required to determine its role in mammalian development.

Mapping of five subtype genes for muscarinic acetylcholine receptor to mouse chromosomes

Abstract: Muscarinic acetylcholine receptors in mammals consist of five subtypes (M1-M5) encoded by distinct genes. They are widely expressed throughout the body and play a variety of roles in the peripheral and central nervous systems. Although their pharmacological properties have been studied extensively in vitro, colocalization of the multiple subtypes in each tissue and lack of subtype-specific ligands have hampered characterization of the respective subtypes in vivo. We have mapped mouse genomic loci for all five genes (Chrm1-5) by restriction fragment length variant (RFLV) analyses in interspecific backcross mice. Chrm1, Chrm2, and Chrm3 were mapped to chromosome (Chr) 19, 6, and 13, respectively. Both Chrm4 and Chrm5 were mapped to Chr 2. Although a comparison of their map positions with other mutations in their vicinities suggested a possibility that the El2 (epilepsy 2) allele might be a mutation in Chrm5, sequencing analyses of the Chrm5 gene in the El2 mutant mice did not support such a hypothesis.

TGF-beta signal transduction.

Abstract: The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.

Cyclooxygenases: Structural, cellular, and molecular biology

Abstract: ▪ Abstract The prostaglandin endoperoxide H synthases-1 and 2 (PGHS-1 and PGHS-2; also cyclooxygenases-1 and 2, COX-1 and COX-2) catalyze the committed step in prostaglandin synthesis. PGHS-1 and 2 are of particular interest because they are the major targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, and the new COX-2 inhibitors. Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. In this review, we examine how the structures of these enzymes relate mechanistically to cyclooxygenase and peroxidase catalysis, and how differences in the structure of PGHS-2 confer on this isozyme differential sensitivity to COX-2 inhibitors. We further examine the evidence for independent signaling by PGHS-1 and PGHS-2, and the complex mechanisms for regulation of PGHS-2 gene expression.

Role of transforming growth factor beta in human disease.

Abstract: In human tissues, normal homeostasis requires intricately balanced interactions between cells and the network of secreted proteins known as the extracellular matrix. These cooperative interactions involve numerous cytokines acting through specific cell-surface receptors. When the balance between the cells and the extracellular matrix is perturbed, disease can result. This is clearly evident in the interactions mediated by the cytokine transforming growth factor β (TGF-β). TGF-β is a member of a family of dimeric polypeptide growth factors that includes bone morphogenic proteins and activins. All of these growth factors share a cluster of conserved cysteine residues that form a common cysteine . . .