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S M Grimmond

Publications and source records attributed to S M Grimmond.

7 recordsLinked to original sources
PubMed2005

Temporal and spatial transcriptional programs in murine kidney development.

We have performed a systematic temporal and spatial expression profiling of the developing mouse kidney using Compugen long-oligonucleotide microarrays. The activity of 18,000 genes was monitored at 24-h intervals from 10.5-day-postcoitum (dpc) metanephric mesenchyme (MM) through to neonatal kidney, and a cohort of 3,600 dynamically expressed genes was identified. Early metanephric development was further surveyed by directly comparing RNA from 10.5 vs. 11.5 vs. 13.5dpc kidneys. These data showed high concordance with the previously published dynamic profile of rat kidney development (Stuart RO, Bush KT, and Nigam SK. Proc Natl Acad Sci USA 98: 5649-5654, 2001) and our own temporal data. Cluster analyses were used to identify gene ontological terms, functional annotations, and pathways associated with temporal expression profiles. Genetic network analysis was also used to identify biological networks that have maximal transcriptional activity during early metanephric development, highlighting the involvement of proliferation and differentiation. Differential gene expression was validated using whole mount and section in situ hybridization of staged embryonic kidneys. Two spatial profiling experiments were also undertaken. MM (10.5dpc) was compared with adjacent intermediate mesenchyme to further define metanephric commitment. To define the genes involved in branching and in the induction of nephrogenesis, expression profiling was performed on ureteric bud (GFP+) FACS sorted from HoxB7-GFP transgenic mice at 15.5dpc vs. the GFP- mesenchymal derivatives. Comparisons between temporal and spatial data enhanced the ability to predict function for genes and networks. This study provides the most comprehensive temporal and spatial survey of kidney development to date, and the compilation of these transcriptional surveys provides important insights into metanephric development that can now be functionally tested.

Animals↗
PubMed2000

Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia.

Vascular endothelial growth factor-B (VEGF-B) is closely related to VEGF-A, an effector of blood vessel growth during development and disease and a strong candidate for angiogenic therapies. To further study the in vivo function of VEGF-B, we have generated Vegfb knockout mice (Vegfb(-/-)). Unlike Vegfa knockout mice, which die during embryogenesis, Vegfb(-/-) mice are healthy and fertile. Despite appearing overtly normal, Vegfb(-/-) hearts are reduced in size and display vascular dysfunction after coronary occlusion and impaired recovery from experimentally induced myocardial ischemia. These findings reveal a role for VEGF-B in the development or function of coronary vasculature and suggest potential clinical use in therapeutic angiogenesis.

Aging↗
PubMed1996

Confirmation of susceptibility locus on chromosome 13 in Australian breast cancer families.

Two major genes determining predisposition to breast cancer, termed BRCA1 and BRCA2, have been mapped to the long arms of chromosomes 17 and 13, respectively. Each locus is believed to account for approximately 40% of cases of familial breast cancer. We used linkage and haplotype analysis with simple tandem repeat polymorphisms at chromosomal bands 17q21 and 13q12 to determine the contribution of the BRCA1 and BRCA2 genes to predisposition to breast cancer in four Australian breast cancer kindreds, one of which had two male cousins with breast cancer. Surprisingly all families segregated a haplotype of markers on 13q and showed positive lod scores supporting linkage to BRCA2. In addition, haplotype analysis identified an informative recombination between D13S260 and D13S171 in one affected individual, which refines the localisation of BRCA2 to between D13S260 and D13S267; a distance of 2-3 cM. Tumours of the stomach and cervix, as well as melanoma and leukaemia/lymphoma also occur in these pedigrees but the numbers are too low to determine whether they may be significantly associated with BRCA2 carrier status. Our results confirm the existence of BRCA2 on the long arm of chromosome 13 and support previous findings that this locus is likely to confer risk in families with affected males. Furthermore, our observations suggest that the BRCA2 gene may also contribute to the development of other neoplasma.

Australia↗
PubMed1996

Predictive diagnosis of multiple endocrine neoplasia (MEN 1) in four Australian kindreds.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN 1) is a tumour predisposition syndrome that usually manifests in the first four decades of life. It has an autosomal dominant mode of inheritance which means that any new member of a MEN1 kindred has roughly a 50% chance of developing the disorder during their lifetime. The localisation of the MEN1 gene to a small region of chromosome band 11q13 has led to the development of DNA-based predictive diagnosis for this disease. AIMS: To establish a polymerase chain reaction (PCR)-based system, using simple tandem repeat polymorphisms (STRPs), to predict gene carriers in four Australian MEN 1 kindreds. METHODS: Six STRP markers flanking the MEN1 region of chromosome band 11q13 were used to screen individuals for a common haplotype in order to determine carrier status. RESULTS: The accuracy of prediction was calculated to be > 95% in informative individuals. CONCLUSIONS: DNA-based presymptomatic detection of affected members of MEN 1 kindreds could facilitate their care and reduce the inconvenience and expense of repeated testing of unaffected members. However, due to occasional recombination events or uninformativeness of markers in certain individuals, carrier status cannot always be predicted.

Adult↗
PubMed1995

G protein mutations in tumours of the pituitary, parathyroid and endocrine pancreas.

A subset of growth-hormone (GH) producing pituitary adenomas harbour mutations at residues Arg201 and Gln227 of the alpha subunit of the stimulatory G protein (Gs alpha). One such mutation has been reported in a GH-producing tumour from a patient with multiple endocrine neoplasia type 1 (MEN 1) although mutations have not been reported in other tumours associated with MEN 1. We used PCR-induced restriction site analysis to screen for these mutations in 80 tumours of the pituitary, parathyroid and endocrine pancreas. Arg201 mutations were detected in 1 non-functioning and 4 GH-producing pituitary tumours. No mutations were found in any of the endocrine tumours tested at Arg179 of the Gi2 alpha subunit, a homologous residue to Arg201 of Gs alpha. Our results indicate oncogenesis in the majority of pituitary and parathyroid tumours is independent of mutations of Gs and Gi2 alpha.

Base Sequence↗
PubMed1992

Detection of a rare point mutation in Ki-ras of a human bladder cancer xenograft by polymerase chain reaction and direct sequencing.

This paper represents the first report of a codon 59 mutation in Ki-ras from a spontaneous human transitional cell carcinoma of the bladder. Point mutations have the potential to activate the ras genes if they occur in critical coding regions. These include the sequences of codons 12, 13, 59, 61 and 63. Mutations in codons 12, 13 and 61 have been reported in a wide variety of human cancers, including transitional cell carcinoma of the bladder. However mutations in codon 59 have been reported only in retroviral Ki-ras and as a result of in vitro mutagenesis experiments. We have used the polymerase chain reaction and direct sequencing to detect mutations of Ki-ras, and allele-specific restriction analysis to detect mutations of N-ras in xenografts and continuous cell lines established from bladder cancer biopsies of ten different patients as well as in direct biopsy specimens from five human bladder tumours. For studies of Ki-ras, a 139 bp fragment which spanned the critical codons 12 and 13 and a 128 bp fragment that spanned the sequences of codon 59, 61 and 63 were enzymatically amplified and then sequenced. No N-ras mutations were detected. A heterozygous mutation of Ki-ras at codon 59 GCA----G/ACA was detected in one line. This mutation is being expressed and appears stable as it was detected over several xenograft passages and was present in paraffin-embedded tissue from the primary tumour of the patient. The biological significance of the mutation in bladder cancer is currently under study.

Animals↗