Biomedical subjects

Eiríkur Steingrímsson

Publications and source records attributed to Eiríkur Steingrímsson.

9 recordsLinked to original sources

PubMed2006

Statistically designing microarrays and microarray experiments to enhance sensitivity and specificity.

Gene expression signatures from microarray experiments promise to provide important prognostic tools for predicting disease outcome or response to treatment. A number of microarray studies in various cancers have reported such gene signatures. However, the overlap of gene signatures in the same disease has been limited so far, and some reported signatures have not been reproduced in other populations. Clearly, the methods used for verifying novel gene signatures need improvement. In this article, we describe an experiment in which microarrays and sample hybridization are designed according to the statistical principles of randomization, replication and blocking. Our results show that such designs provide unbiased estimation of differential expression levels as well as powerful tests for them.

Breast Neoplasms↗

PubMed2006

Mouse coat color mutations: from fancy mice to functional genomics.

Mouse coat color mutations have a long history in biomedical research. The viable and visible phenotype of most coat color mutations has made the pigment cell, the melanocyte, an ideal system for genetic, molecular, and cellular analysis. Molecular cloning and analysis of many of the different coat color mutations have revealed the roles of a diverse range of genes, and today we know more about the pathways and proteins that regulate the development and function of pigment cells than we know about most other cell types in mammalian organisms. Coat color mutations have also provided novel insights into stem cell biology and human diseases, including melanoma. In the future, it will be important to build on this history and knowledge by taking advantage of the extensive repertoire of recently developed genome-wide methodologies, available genomic information, and the powerful methods that have been developed for modifying the mouse genome to systematically dissect the development and function of this important cell type. The usefulness of coat color mutations has just begun to emerge.

Animals↗

PubMed2005

Melanocyte stem cell maintenance and hair graying.

Hair graying is an obvious sign of human aging, yet little was known about its causes. Two recent papers provide compelling evidence that hair graying is due to incomplete melanocyte stem cell maintenance and identify Pax3 and Mitf as key molecules that help regulate the balance between melanocyte stem cell maintenance and differentiation.

Aging↗

PubMed2004

Electroretinographic assessment of retinal function in microphthalmia mutant mice.

The purpose of this study was to examine the effects of mutations in the mouse (Mus musculus) multi-allelic microphthalmia transcription factor (Mitf) gene on retinal function. Mitf mice provide a rare opportunity to assess retinal degeneration caused by defective retinal pigment epithelium (RPE). Electroretinography (ERG) was used to evaluate the functional state of the retina and to determine the role of the Mitf gene in visual function. Corneal ERGs were recorded with a steel wire in response to white flashes of light. Homozygous Mitf(Mi-wh)/Mitf(Mi-wh), Mitf(mi-sp)/Mitf(mi-sp) Mitf(mi-bws)/Mitf(mi-bws) and wild type mice in addition to Mitf(Mi-wh)/Mitf(mi-sp) compound heterozygous mutants were studied at 16 weeks of age. Although each animal was only tested once, multiple animals of each genotype were tested. The ERGs of Mitf(mi-sp)/Mitf(mi-sp) were found to be normal. All components of the ERGs of Mitf(mi-bws)/Mitf(mi-bws) mice were normal except the photopic b-wave and the scotopic c-wave, which were reduced in amplitude. The ERGs of Mitf(Mi-wh)/Mitf(Mi-wh) mice suggest they are probably blind. On the other hand, ERGs from Mitf(Mi-wh)/Mitf(mi-sp) mice were reduced in amplitude and delayed, indicating an RPE/photoreceptor defect. At 16 weeks post partum, Mitf(Mi-wh)/Mitf(mi-sp) mutants show evidence of rod-cone dystrophy. Surprisingly, Mitf(mi-bws)/Mitf(mi-bws) mice, which have a similar phenotype as Mitf(mi-vit) mice with respect to coat color and eye development, show mostly normal ERGs. The reduced scotopic c-wave in Mitf(mi-bws)/Mitf(mi-bws) mice, without reduction in the scotopic a-wave indicates an RPE defect without photoreceptor involvement in these mice.

Animals↗

PubMed2004

The novel mouse microphthalmia mutations Mitfmi-enu5 and Mitfmi-bcc2 produce dominant negative Mitf proteins.

Mutations in the microphthalmia-associated transcription factor (Mitf) gene affect the development of different cell types, including melanocytes, osteoclasts, and retinal pigmented epithelial cells of the eye. Many different mutations at the locus are known and since they affect the phenotype to different extents they form an allelic series. The Mitf protein is a member of the Mitf-Tfe subfamily of basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factors and binds the 6-bp canonical CAC/TGTG sequence (E box) as either a homodimer or a heterodimer with related proteins. The many Mitf mutations have provided important insights into the in vivo behavior of a bHLH-Zip protein. Here we describe the phenotype of two new semidominant Mitf mutations recovered in recent mutagenic screens, Mitf(mi-enu5) and Mitf(mi-bcc2); determine the molecular lesions involved; and show that the mutant proteins act in a dominant negative fashion in vitro. The novel mutations are phenotypically distinct from previously known Mitf mutations.

Amino Acid Sequence↗

PubMed2004

Melanocytes and the microphthalmia transcription factor network.

The first mouse microphthalmia transcription factor (Mitf ) mutation was discovered over 60 years ago, and since then over 24 spontaneous and induced mutations have been identified at the locus. Mitf encodes a member of the Myc supergene family of basic helix-loop-helix zipper (bHLH-Zip) transcription factors. Like Myc, Mitf regulates gene expression by binding to DNA as a homodimer or as a heterodimer with another related family member, in the case of Mitf the Tfe3, Tfeb, and Tfec proteins. The study of Mitf has provided many insights into the biology of melanocytes and helped to explain how melanocyte-specific gene expression and signaling is regulated. The human homologue of MITF is mutated in patients with the pigmentary and deafness disorder Waardenburg Syndrome Type 2A (WS2A). The mouse Mitf mutations therefore serve as a model for the study of this human disease. Mutations and/or aberrant expression of several MITF family member genes have also been reported in human cancer, including melanoma (MITF), papillary renal cell carcinoma (TFE3, TFEB), and alveolar soft part sarcoma (TFE3). Genes in the MITF/TFE pathway may therefore also represent valuable therapeutic targets for the treatment of human cancer. Here we review recent developments in the analysis of Mitf function in vivo and in vitro and show how traditional genetics, modern forward genetics and in vitro biochemical analyses have combined to produce an intriguing story on the role and actions of a gene family in a living organism.

Alleles↗

PubMed2004

The basic helix-loop-helix leucine zipper transcription factor Mitf is conserved in Drosophila and functions in eye development.

The MITF protein is a member of the MYC family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors and is most closely related to the TFE3, TFEC, and TFEB proteins. In the mouse, MITF is required for the development of several different cell types, including the retinal pigment epithelial (RPE) cells of the eye. In Mitf mutant mice, the presumptive RPE cells hyperproliferate, abnormally express the retinal transcriptional regulator Pax6, and form an ectopic neural retina. Here we report the structure of the Mitf gene in Drosophila and demonstrate expression during embryonic development and in the eye-antennal imaginal disc. In vitro, transcriptional regulation by Drosophila Mitf, like its mouse counterpart, is modified by the Eyeless (Drosophila Pax6) transcription factor. In vivo, targeted expression of wild-type or dominant-negative Drosophila Mitf results in developmental abnormalities reminiscent of Mitf function in mouse eye development. Our results suggest that the Mitf gene is the original member of the Mitf-Tfe subfamily of bHLH-Zip proteins and that its developmental function is at least partially conserved between vertebrates and invertebrates. These findings further support the common origin of the vertebrate and invertebrate eyes.

Alleles↗

PubMed2003

Interallelic complementation at the mouse Mitf locus.

Mutations at the mouse microphthalmia locus (Mitf) affect the development of different cell types, including melanocytes, retinal pigment epithelial cells of the eye, and osteoclasts. The MITF protein is a member of the MYC supergene family of basic-helix-loop-helix-leucine-zipper (bHLHZip) transcription factors and is known to regulate the expression of cell-specific target genes by binding DNA as homodimer or as heterodimer with related proteins. The many mutations isolated at the locus have different effects on the phenotype and can be arranged in an allelic series in which the phenotypes range from near normal to white microphthalmic animals with osteopetrosis. Previous investigations have shown that certain combinations of Mitf alleles complement each other, resulting in a phenotype more normal than that of each homozygote alone. Here we analyze this interallelic complementation in detail and show that it is limited to one particular allele, Mitf(Mi-white) (Mitf(Mi-wh)), a mutation affecting the DNA-binding domain. Both loss- and gain-of-function mutations are complemented, as are other Mitf mutations affecting the DNA-binding domain. Furthermore, this behavior is not restricted to particular cell types: Both eye development and coat color phenotypes are complemented. Our analysis suggests that Mitf(Mi-wh)-associated interallelic complementation is due to the unique biochemical nature of this mutation.

Animals↗

PubMed2003

[Stem cells: cell differentiation and novel therapies.].

Stem cells are unusual with regard to their capability of both self-renewal and differentiation into specialized cells. Best known are the hematopoietic stem cells which have been used in cell replacement therapy for many years. Recently, research on both embryonic and adult stem cells has offered new hope of cell replacement therapy to treat various diseases. Here we review the properties of both embryonic and adult stem cells as well as recent experiments on the therapeutic use of such cells. Although stem cells offer promising solutions for medical treatment, many difficulties need to be overcome before laboratory results can be moved to the bedside.

English Abstract↗