The MurineFem1Gene Family: Homologs of theCaenorhabditis elegansSex-Determination Protein FEM-1

Ventura-Holman, Tereza; Seldin, Michael F.; Li, Wenhui; Maher, Joseph F.

doi:10.1006/geno.1998.5569

Cited by 49 publications

(38 citation statements)

References 43 publications

(45 reference statements)

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“…However, a search in the EST data base from NCBI has revealed several human and murine cDNA clones that share high level of similarity (Ͼ30%) in amino acid sequence with F1A, suggesting F1A might be a member of a gene family. During the preparation of this manuscript, the deduced amino acid sequence of two members, Fem1a and Fem1b, of a mouse gene family was reported (43). The amino acid sequence of Fem1b is identical to that of mF1A confirming that F1A is indeed a member of a gene family.…”

Section: Resultsmentioning

confidence: 87%

F1Aα, a Death Receptor-binding Protein Homologous to theCaenorhabditis elegans Sex-determining Protein, FEM-1, Is a Caspase Substrate That Mediates Apoptosis

Chan

Tan²,

Zhang³

et al. 1999

Journal of Biological Chemistry

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Apoptosis is an evolutionarily conserved process that is critical for tissue homeostasis and development including sex determination in essentially all multicellular organisms. Here, we report the cloning of an ankyrin repeat-containing protein, termed F1A␣, in a yeast twohybrid screen using the cytoplasmic domain of Fas (CD95/APO-1) as bait. Amino acid sequence analysis indicates that F1A␣ has extensive homology to the sexdetermining protein FEM-1 of the Caenorhabditis elegans, which is required for the development of all aspects of the male phenotype. F1A␣ associates with the cytoplasmic domains of Fas and tumor necrosis factor receptor 1, two prototype members of the "death receptor" family. The F1A␣ protein also oligomerizes. Overexpression of F1A␣ induces apoptosis in mammalian cells, and co-expression of Bcl-XL or the dominant negative mutants of either FADD or caspase-9 blocks this effect. Deletion analysis revealed the center region of F1A␣, including a cluster of five ankyrin repeats to be necessary and sufficient for maximum apoptotic activity, and the N-terminal region appears to regulate negatively this activity. Furthermore, F1A␣ is cleaved by a caspase-3-like protease at Asp 342 , and the cleavage-resistant mutant is unable to induce apoptosis upon overexpression.

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Section: Resultsmentioning

confidence: 87%

F1Aα, a Death Receptor-binding Protein Homologous to theCaenorhabditis elegans Sex-determining Protein, FEM-1, Is a Caspase Substrate That Mediates Apoptosis

Chan

Tan²,

Zhang³

et al. 1999

Journal of Biological Chemistry

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“…We used gene targeting by homologous recombination (25) to generate Fem1b-KO mice with a deletion of Fem1b coding exon 1, which contains the translation initiation codon and the first two ankyrin repeats (36). This approach utilized standard methodology, and the basic elements of the targeting vector and screening strategy by Southern blot and PCR genotyping are shown (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A mammalian Fem1 gene family, encoding homologs of fem-1, has been characterized and consists of at least three members in the mouse, designated Fem1a, Fem1b, and Fem1c; these have highly conserved homologs in humans, designated FEM1A, FEM1B, and FEM1C, respectively (4,22,(36)(37)(38)(39). A mammalian Fem1 transgene expressed in fem-1 mutants of C. elegans causes partial rescue of masculinization, suggesting evolutionary conservation of ancient biochemical signaling interactions (36). However, the biochemical mechanisms of nematode fem-1 gene action remain unknown, and in vivo physiologic functions of the mammalian Fem1 genes have not yet been defined.…”

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confidence: 99%

Abnormal Glucose Homeostasis and Pancreatic Islet Function in Mice with Inactivation of the Fem1b Gene

Ventura-Holman

et al. 2005

Molecular and Cellular Biology

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Type 2 diabetes mellitus is a disorder of glucose homeostasis involving complex gene and environmental interactions that are incompletely understood. Mammalian homologs of nematode sex determination genes have recently been implicated in glucose homeostasis and type 2 diabetes mellitus. These are the Hedgehog receptor Patched and Calpain-10, which have homology to the nematode tra-2 and tra-3 sex determination genes, respectively. Here, we have developed Fem1b knockout (Fem1b-KO) mice, with targeted inactivation of Fem1b, a homolog of the nematode fem-1 sex determination gene. We show that the Fem1b-KO mice display abnormal glucose tolerance and that this is due predominantly to defective glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion is also affected. The Fem1b gene is expressed in pancreatic islets, within both ␤ cells and non-␤ cells, and is highly expressed in INS-1E cells, a pancreatic ␤-cell line. In conclusion, these data implicate Fem1b in pancreatic islet function and insulin secretion, strengthening evidence that a genetic pathway homologous to nematode sex determination may be involved in glucose homeostasis and suggesting novel genes and processes as potential candidates in the pathogenesis of diabetes mellitus.

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“…Fem1c is so named because the amino acid identity (similarity) is 69% (83%) and 41% (60%) compared with the amino acids of the mouse Fem1a and Fem1b genes, respectively. Together, the members of this family of genes share significant homology to the sexdetermining fem-1 gene of C. elegans, particularly in the presence of a series of seven ankyrin motifs located near the N terminus and the sequence PXXLXXFXXXH at the C terminus (14,31,32). In C. elegans, fem-1 is essential for the development of male worms (both in masculinizing somatic cells and in the production of sperm in males and hermaphrodites) (7,13).…”

Section: Discussionmentioning

confidence: 99%

Insertion of the βGeo Promoter Trap into the Fem1c Gene of ROSA3 Mice

Schlamp

Thliveris

et al. 2004

Molecular and Cellular Biology

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ROSA3 mice were developed by retroviral insertion of the ␤Geo gene trap vector. Adult ROSA3 mice exhibit widespread expression of the trap gene in epithelial cells found in most organs. In the central nervous system the highest expression of ␤Geo is found in CA1 pyramidal cells of the hippocampus, Purkinje cells of the cerebellum, and ganglion cells of the retina. Characterization of the genomic insertion site for ␤Geo in ROSA3 mice shows that the trap vector is located in the first intron of Fem1c, a gene homologous to the sex-determining gene fem-1 of Caenorhabditis elegans. Transcription of the Rosa3 allele (R3) yields a spliced message that includes the first exon of Fem1c and the ␤Geo coding region. Although normal processing of the Fem1c transcript is disrupted in homozygous Rosa3 (Fem1c R3/R3 ) mice, some tissues show low levels of a partially processed transcript containing exons 2 and 3. Since the entire coding region of Fem1c is located in these two exons, Fem1c R3/R3 mice may still be able to express a putative FEM1C protein. To this extent, Fem1c R3/R3 mice show no adverse effects in their sexual development or fertility or in the attenuation of neuronal cell death, another function that has been attributed to both fem-1 and a second mouse homolog, Fem1b. Examination of ␤Geo expression in ganglion cells after exposure to damaging stimuli indicates that protein levels are rapidly depleted prior to cell death, making the ␤Geo reporter gene a potentially useful marker to study early molecular events in damaged neurons.Promoter trap experiments using the reverse orientation splice acceptor (ROSA) ␤Geo retroviral gene trap vector (9) have been useful in identifying genes involved in mouse development (4, 5). The coding region for the trap vector contains bacterial ␤-galactosidase fused in frame to neomycin phosphotransferase (Neo) to produce a fusion protein (␤Geo) that processes substrates like X-Gal (5-bromo-4-chloro-3-indolyl-␤-D-galactopyranoside) and neomycin. Transcription of ␤Geo is dependent on the trap vector being inserted into the vicinity of an existing gene in the mouse genome, where the presence of a 5Ј splice acceptor facilitates the splicing of the ␤Geo coding region into the nearest upstream exon. The ROSA3 line of mice was initially part of 31 lines established using retroviral insertion of the ␤Geo vector into embryonic stem cells (9). The insertion of the ␤Geo gene caused embryonic recessive lethality in some of the lines. ROSA3 mice showed no overt defects, however, and exhibited a widespread pattern of staining by embryonic day 12.Here, we report the further characterization of the ROSA3 line of mice. As with the results seen with the embryos, ROSA3 mouse adult tissues show widespread staining (including selective staining of certain populations of neurons in the central nervous system) in ␤-galactosidase assays. Analysis of the genomic insertion site shows that the ␤Geo gene has been inserted into the first intron of Fem1c, the third member of a murine gene family that shares homolo...

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The MurineFem1Gene Family: Homologs of theCaenorhabditis elegansSex-Determination Protein FEM-1

Cited by 49 publications

References 43 publications

F1Aα, a Death Receptor-binding Protein Homologous to theCaenorhabditis elegans Sex-determining Protein, FEM-1, Is a Caspase Substrate That Mediates Apoptosis

F1Aα, a Death Receptor-binding Protein Homologous to theCaenorhabditis elegans Sex-determining Protein, FEM-1, Is a Caspase Substrate That Mediates Apoptosis

Abnormal Glucose Homeostasis and Pancreatic Islet Function in Mice with Inactivation of the Fem1b Gene

Insertion of the βGeo Promoter Trap into the Fem1c Gene of ROSA3 Mice

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