SEARCH · PubMed Health

Results for “Phenotype modifier”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 631 records · Page 35Linked to original sources

PubMed2005

Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer.

Hsp90 is a chaperone for over 100 'client proteins' in the cell, most of which are involved in signaling pathways. For example, Hsp90 maintains several nuclear hormone receptors, such as the estrogen receptor (ER), as agonist-receptive monomers in the cytoplasm. In the presence of agonist, Hsp90 dissociates and the receptors dimerize, enter the nucleus and ultimately activate transcription of the target genes. Increasing evidence suggests that Hsp90 also has a role in modifying the chromatin conformation of many genes. For example, Hsp90 has recently been shown to increase the activity of the histone H3 lysine-4 methyltransferase SMYD3, which activates the chromatin of target genes. Further evidence for chromatin-remodeling functions is that Hsp90 acts as a capacitor for morphological evolution by masking epigenetic variation. Release of the capacitor function of Hsp90, such as by environmental stress or by drugs that inhibit the ATP-binding activity of Hsp90, exposes previously hidden morphological phenotypes in the next generation and for several generations thereafter. The chromatin-modifying phenotypes of Hsp90 have striking similarities to the trans-generational effects of the ER agonist diethylstilbesterol (DES). Prenatal and perinatal exposure to DES increases the predisposition to uterine developmental abnormalities and cancer in the daughters and granddaughters of exposed pregnant mice. In this review, we propose that trans-generational epigenetic phenomena involving Hsp90 and DES are related and that chromatin-mediated WNT signaling modifications are required. This model suggests that inhibitors of Hsp90, WNT signaling and chromatin-remodeling enzymes might function as anticancer agents by interfering with epigenetic reprogramming and canalization in cancer stem cells.

Animals↗

PubMed1994

Contribution of transplantations to the understanding of the role of the PLP gene.

We present an overview of the results obtained in a cross-transplantation system using respectively controls, jimpy (jp), and shiverer mutant mice as donors and recipients. Homochronic transplantations (O days into O days) demonstrated that jp environment is non-toxic for non-jp cells and that, contrary to in vitro, jp oligodendrocytes phenotype cannot be modified by environmental factors at this age. Transplantations of embryonic fragments into the newborn brain demonstrated that in contrast to oligodendrocyte precursors contained in fragments of newborn tissue, jimpy embryonic stem cells are sensitive to environmental factors able to modulate the proportion of surviving oligodendrocytes. In addition, these series evidenced a disjunction between the surviving and the myelinating capacity of jp cells demonstrating a pleiotropic effect of the jp mutation on oligodendrocyte biology. Results are discussed with regards to the recent molecular biological finding on the role of the DM20/PLP gene.

Animals↗

PubMed1997

Apert's syndrome: differential in vitro production of matrix macromolecules and its regulation by interleukins.

During embryonic development, variations in the composition of the extracellular matrix (ECM) macromolecules influence bone tissue differentiation. We present novel findings on the in vitro phenotypic expression of periosteal fibroblasts obtained from patients affected by Apert's syndrome, a rare craniofacial malformation, and the effects that interleukins (ILs) induce on the phenotype. Apert fibroblasts synthesized greater quantities of glycosaminoglycans (GAGs) and intracellular type I collagen, and also produced more type III collagen and fibronectin. The amount of hyaluronic acid (HA) secreted by Apert fibroblasts was much higher than that secreted by normal fibroblasts, but, as the absolute values of heparan sulphate (HS), chondroitin sulphate (CS) and dermatan sulphate (DS) also rose in Apert media, the HA-sulphated GAG ratio was similar in the media obtained from both populations. Both ILs triggered elevations of HA in normal cells, although relative percentage secretion remained unaltered, but significantly reduced HA secretion by Apert cells. IL-1 significantly increased CS in normal and Apert media, whereas IL-6 enhanced HS and DS in media of both populations. HA-sulphated GAG ratio decreased in Apert media after IL treatment. Both ILs boosted fibronectin production by Apert fibroblasts, whereas IL-1 increased type III but not type I collagen. Taken together, these data demonstrate that the synthesis and secretion of ECM macromolecules are markedly altered in Apert fibroblasts. The fact that treatment with ILs further modifies the Apert phenotype suggests that ILs may be implicated in the pathophysiology of the malformations during skull morphogenesis.

Acrocephalosyndactylia↗

PubMed1991

Male-sex-ratio trait in Drosophila pseudoobscura: frequency of autosomal aneuploid sperm.

Males with the SR X chromosome show the "sex-ratio" (sr) phenotype in which they produce almost entirely daughters. The few sons (about 1%) are invariably sterile X/O males and result entirely from nullo-XY sperm. The "male-sex-ratio" (msr) phenotype is a modified form of sr in which SR/Y males produce a higher frequency of sterile X/O sons. The msr trait is due to the presence of the SR X-chromosome in males which are also homozygous for one or more autosomes from the L116 strain. Here the frequency of nullo-3 and diplo-3 sperm from msr males was measured by crossing to a compound-3 strain and found to be 13.8% and 3.2%, respectively, of the total viable sperm. The sr males produced very low levels of nullo-3 sperm at a frequency not different from control X/Y males and a slightly elevated frequency of diplo-3 sperm over X/Y males. The msr males were found to have only 12% the fecundity of sr males and in matings to cause a high frequency of brown inviable eggs. These results indicate that high rates of autosomal aneuploidy are not restricted to chromosome 3 but also occur for chromosomes 2, 4 and 5. The overall frequency of autosomal aneuploid sperm is estimated to be approximately 50%. Microscopic studies of meiosis in testes from msr males indicates meiotic nondisjunction and meiotic chromosome loss are responsible for the msr phenotype. Last, microscopic studies of sperm cysts from msr males reveal high levels of spermiogenic failure.

Anaphase↗

PubMed2005

The use of behavioral test batteries, II: effect of test interval.

Test batteries are commonly used to assess the behavioral phenotype of genetically modified and inbred strains of mice. However, few systematic studies have been employed to address several key issues concerning the use of a test battery. The current study was designed to address whether inter-test interval affects behavioral performance. Male mice of 3 different inbred strains and one F1 hybrid strain were randomly assigned to either a test battery with 1 week inter-test intervals, or a rapid test battery with 1-2 day inter-test intervals. The test battery included a neurological exam, open-field activity, light-dark exploration, rotarod test, prepulse inhibition, and startle habituation. The experiment was repeated with female animals of 2 different strains. As expected, there were strain differences on each of the behavioral assays; however, there was no major difference in performance between mice of the standard test battery and the rapid test battery. Similar results were found with females. These results indicate that the interval between most tests could be as little as 1-2 days, with little significant effect on overall performance. Thus, it is possible with the current test battery to reduce the inter-test interval to facilitate the rate of studying and identifying behavioral phenotypes in mice.

Analysis of Variance↗

PubMed2005

Electrophysiological and behavioral phenotype of insulin receptor defective mice.

The olfactory bulb expresses one of the highest levels of insulin found in the brain. A high level of expression of the concomitant insulin receptor (IR) kinase is also retained in this brain region, even in the adult. We have previously demonstrated in a heterologous system that insulin modulates the voltage-dependent potassium channel, Kv1.3, through tyrosine phosphorylation of three key residues in the amino and carboxyl terminus of the channel protein. Phosphorylation also induces current suppression of the Kv1.3-contributed current in cultured olfactory bulb neurons (OBNs) of rodents. In order to explore the behavioral importance of this kinase-induced modulation of the channel for the olfactory ability of the animal, mice with a targeted-gene deletion of the insulin receptor were electrophysiologically and behaviorally characterized. Mice heterozygous for the insulin receptor kinase (IR+/-) gene performed the same as wild-type (+/+) mice when challenged with a traditional, non-learning-based task to test gross anosmia. There was also no significant difference across the two genotypes in tests designed to measure exploratory behavior or in a battery of systems physiology experiments designed to assess metabolic energy usage (locomotion, ingestive behaviors, weight, oxygen consumption, and respiratory quotient). Object memory recognition tests suggest that IR+/- mice have an impairment in recognition of familiarized objects; IR+/- mice demonstrate poor performance for both short-term (1 h) and long-term (24 h) memory tests in comparison to that of wild-type mice. Electrophysiological experiments indicate that mitral cell neurons cultured from both heterozygous and homozygous-null mice (IR+/- and IR-/-) have an decreased peak current amplitude compared with that recorded for wild-type (+/+) animals matched for days in vitro (DIV). These data indicate that the loss of one allele of the IR kinase gene modifies the electrical phenotype of the mitral cell neurons in the olfactory bulb without a change in gross olfactory ability. Given our findings that there are no significant changes in metabolic balance of the IR (+/-) mice but some impairment in memory retention, future experiments testing for specific olfactory behaviors or functional deficits in IR-/+ mice models of diabetes will need to either be tasks that do not require learning or will require a different model (such as diet-induced diabetes) that may evoke a stronger phenotype.

Animals↗

PubMedDate not supplied

[Clinical and cytogenetic variability in 12 Mexican families with Fanconi's anemia and its relationship with the complement gruoup to which they belong].

OBJECTIVE: To describe the clinical and cytogenetic features of Mexican patients with Fanconi anemia, while assessing whether the phenotypic variation is related to the complementation group. MATERIAL AND METHODS: The cytogenetic diagnosis was done using mitomycin C and diepoxybutane on peripheral blood lymphocytes. The severity of the anemia and each patient's clinical manifestations were classified using Alter's and Auerbach's clinical scores, respectively. Lymphoblastoid cell lines were established for eight patients and complementation group determined following cell fusion procedures in four propositi. RESULTS: Twenty-five Fanconi anemia patients from 12 families were studied. All patients had high, spontaneous and induced chromosomal breakages, no relationship was found between the clinical severity of the disease and the anemic state. Twelve patients were considered severely ill, while the remaining 13 were considered mild cases. Three individuals were anemia-free, while in 13 the anemia was mild, moderate in 7, and severe in 1. The mortality rate was 32% (8/25). No relationship was found between the clinical picture and degree of the anemia or mortality rate. Eleven patients were assigned to complementation group A with mild clinical findings and anemia. Their cytogenetic results showed variability. One patient assigned to group C was considered as a severe case with transfusion-dependent anemia and high sensitivity to mutagens. Thirteen patients were not classified. A lymphoblastoid cell line resistant to mitomycin C was obtained suggesting somatic mosaicism. CONCLUSIONS: The establishment of a complementation group does not necessarily explain variability. There are other important factors, such as somatic mosaicism, that modify the cellular phenotype.

Chromosome Aberrations↗

PubMed1996

Tunicamycin potentiates drug cytotoxicity and vincristine retention in multidrug resistant cell lines.

Tunicamycin (TM), an inhibitor of glycoprotein processing, was investigated for its potential to reverse the multiple drug resistance (MDR) phenotype. When TM was added in vitro to drug-resistant NIH-3T3-MDR and KB-8-5-11 cells, they developed an increased sensitivity to doxorubicin, epirubicin, vincristine and colchicine. Similarly, the sensitivity of NIH-3T3-MDR cells to cisplatin was also enhanced by TM. In the presence of TM, drug-sensitive NIH-3T3-parental cells exhibited greater susceptibility to the toxic effects of doxorubicin, epirubicin, vincristine (marginally significant), and colchicine, but not to cisplatin. Tunicamycin-treated drug-sensitive KB-3-1 cells showed an increased response to vincristine, but not to the other anticancer drugs. Pretreatment with TM inhibited glycoprotein synthesis in all the cell lines. Neither prior exposure to, nor co-incubation with TM, influenced the uptake of vincristine (VCR) in the various cell lines. However, NIH-3T3-MDR cells accumulated less VCR than their drug-sensitive controls and also exhibited reduced efflux of the drug when treated with TM. There were no significant differences in the levels of intracellular VCR uptake between drug-sensitive KB-3-1 and KB-8-5-11 cells. Tunicamycin increased intracellular VCR retention in KB-8-5-11 and NIH-3T3-MDR cells, but not in NIH-3T3-parental cells. However, drug-sensitive KB-3-1 cells expressed reduced VCR retention in response to TM exposure, indicating that correlations between VCR toxicity and its retention in the presence of TM should be made with caution. The results suggest that the enhancement of intracellular VCR retention in MDR cells lines caused by TM is likely to be the result of inhibition of VCR efflux. Inhibition of glycoprotein synthesis during TM exposure may account for the changes in VCR efflux and retention observed in the MDR cell lines. The enhancement of cisplatin cytotoxicity in NIH-3T3-MDR cells after exposure to TM is an interesting observation, since it is generally believed that agents which modify the MDR phenotype do not show a sensitising effect to cisplatin. These findings may have applications in the reversal of drug resistance.

Antineoplastic Agents↗

PubMed1998

Identification of a candidate modifying gene for spinal muscular atrophy by comparative genomics.

Spinal muscular atrophy (SMA) is a common recessive disorder characterized by the loss of lower motor neurons in the spinal cord. The disease has been classified into three types based on age of onset and severity. SMA I-III all map to chromosome 5q13 (refs 2,3), and nearly all patients display deletions or gene conversions of the survival motor neuron (SMN1) gene. Some correlation has been established between SMN protein levels and disease course; nevertheless, the genetic basis for SMA phenotypic variability remains unclear, and it has been postulated that the loss of an additional modifying factor contributes to the severity of type I SMA. Using comparative genomics to screen for such a factor among evolutionarily conserved sequences between mouse and human, we have identified a novel transcript, H4F5, which lies closer to SMN1 than any previously identified gene in the region. A multi-copy microsatellite marker that is deleted in more than 90% of type I SMA chromosomes is embedded in an intron of this gene, indicating that H4F5 is also highly deleted in type I SMA chromosomes, and thus is a candidate phenotypic modifier for SMA.

Amino Acid Sequence↗

PubMed2000

Application of a modified selection index for honey bees (Hymenoptera: Apidae).

Nine different genetic families of honey bees (Apis mellifera L.) were compared using summed z-scores (phenotypic values) and a modified selection index (Imod). Imod values incorporated both the phenotypic scores of the different traits and the economic weightings of these traits, as determined by a survey of commercial Ontario beekeepers. Largely because of the high weight all beekeepers place on honey production, a distinct difference between line rankings based on phenotypic scores and Imod scores was apparent, thereby emphasizing the need to properly weight the traits being evaluated to select bee stocks most valuable for beekeepers. Furthermore, when beekeepers who made >10% of their income from queen and nucleus colony sales assigned relative values to the traits used in the Imod calculations, the results differed from those based on weightings assigned by honey producers. Our results underscore the difficulties the North American beekeeping industry must overcome to devise effective methods of evaluating colonies for breeding purposes.

Animals↗

PubMed1996

Interaction between mutations in the suppressor of Hairy wing and modifier of mdg4 genes of Drosophila melanogaster affecting the phenotype of gypsy-induced mutations.

The suppressor of Hairy-wing [su(Hw)] protein mediates the mutagenic effect of the gypsy retrotransposon by repressing the function of transcriptional enhancers located distally from the promoter with respect to the position of the su(Hw)-binding region. Mutations in a second gene, modifier of mdg4, also affect the gypsy-induced phenotype. Two major effects of the mod(mdg4)1u1 mutation can be distinguished: the interference with insulation by the su(Hw)-binding region and direct inhibition of gene expression that is not dependent on the su(Hw)-binding region position. The mod(mdg4)1u1 mutation partially suppresses ct6, scD1 and Hw1 mutations, possibly by interfering with the insulation effect of the su(Hw)-binding region. An example of the second effect of mod(mdg4)1u1 is a complete inactivation of yellow expression in combination with the y2 allele. Phenotypic analyses of flies with combinations of mod(mdg4)1u1 and different su(Hw) mutations, or with constructions carrying deletions of the acidic domains of the su(Hw) protein, suggest that the carboxy-terminal acidic domain is important for direct inhibition of yellow transcription in bristles, while the amino-terminal acidic domain is more essential for insulation.

Animals↗

PubMed1998

ApoE genotype is a risk factor in nonpresenilin early-onset Alzheimer's disease families.

The apolipoprotein E (ApoE) genotype is a significant risk factor and modulator of age of onset of Alzheimer's disease (AD). We analyzed the effect of the ApoE genotype in two distinct early-onset familial AD groups: families with a mutation in the presenilin-1 gene (PS-1) on chromosome 14, and families without a mutation detectable in the PS-1, presenilin-2 (PS-2), and the amyloid precursor protein (APP) gene (non-PS early-onset familial AD). The ApoE genotype is clearly shown not to modulate age of onset in families with a mutation in the PS-1 gene and families with no lesion detectable in either the presenilin or APP gene. The effects of a double dose of ApoE4 on age of onset were not assessed in the PS-1 AD families due to the lack of any affected ApoE4 homozygotes in the sample set; this insufficiency will need to be assessed in further studies. There was no association between the ApoE4 allele and AD in the PS-1 families. Non-PS early-onset AD families were shown to have a significantly higher frequency of ApoE4 compared to controls and the PS-1 AD group. These observations are important and suggest that 1) other genetic and environmental factors modify the AD phenotype in PS-1 and non-PS early-onset families; and 2) the ApoE4 allele is a significant risk factor in the etiology of non-PS early-onset AD and will be a useful adjunct in the diagnosis of unaffected family members.

Alleles↗

PubMed1997

Suppression of metastatic potential and up-regulation of gelatinases and uPA in LLC by protracted in vivo treatment with dacarbazine or razoxane.

Treatment of mouse Lewis lung carcinoma with razoxane or dacarbazine was protracted for 10 transplant generations. While the capacity of the treated tumors to grow locally in immuno-competent or in immuno-depressed hosts was retained and not significantly modified, the metastatic phenotype was eliminated when the treated tumor cells were transplanted into immuno-competent hosts. The reduction in metastatic potential was slightly less pronounced, in terms of both number and volume of metastases, when the treated tumor cells were transplanted into immuno-depressed hosts. These properties were retained after 3 transplant generations without treatment. Northern blotting and zymography of primary-tumor crude extracts revealed that treatment with either razoxane or dacarbazine for one generation approximately doubled the expression of MMP-2 and MMP-9, while lacking any effect on that of 1.0 and of 3.5 kb TIMP-2. When the treatment was maintained for 10 generations, the expression of MMP-2 and MMP-9 for both drugs showed up-regulation of approximately 10- and 2-fold respectively. TIMP-2 mRNA of 1.0 kb doubled its expression, while that of 3.5 kb registered just above the control. Dacarbazine doubled the expression of uPA after 10 generations, while razoxane boosted it approximately 3-fold after either 1 or 10 generations. The permanent loss of metastatic phenotype induced in Lewis lung carcinoma by dacarbazine and razoxane is thus attributable to biological mechanisms independent of down-regulation of expression and/or activation of the 2 gelatinases.

Animals↗

PubMed1989

Molecular genetics of Delta, a locus required for ectodermal differentiation in Drosophila.

Delta (Dl) is one of the six known zygotic neurogenic genes, each of which is essential for proper segregation of the embryonic ectoderm into neural and epidermal lineages. Molecular analysis of Dl reveals that it is a transcriptionally complex locus that yields multiple maternal and zygotic transcripts. DNA sequence analysis suggests that the predominant product of the locus is a putative transmembrane protein exhibiting homology to blood coagulation factors and epidermal growth factor of vertebrates. The structure of this product is consistent with the hypothesis that Dl participates in cell-cell interactions that are central to establishment of the epidermal lineage within the developing ectoderm. Genetic analyses demonstrate that Dl mutations can modify the imaginal phenotypes that result from heterozygosity for Notch (N) mutations as well as the interaction between particular alleles of Notch (N) and Enhancer of split [E(spl)], two other members of the neurogenic gene set. Vital interactions also occur between Dl and N. Given the structures of products encoded by N, Dl, and E(spl), we suggest that the synergistic phenotypic interactions observed among mutations in these three loci result from physical, as opposed to regulatory, interactions.

Alleles↗

PubMed1995

Two-dimensional electrophoresis of intracellular and secreted protein synthesized by fetal bovine chondrocytes in high-density culture.

In order to study the mechanisms involved in the differentiation/dedifferentiation of chondrocytes, fetal bovine chondrocytes in high-density cultures were treated with retinoic acid, an agent known to modify the chondrocyte phenotype (10 mumol/L between day 2 to day 5 of culture). The synthesis of intracellular and secreted proteins was studied by two-dimensional electrophoresis in cell lysates and culture media after labeling with [35S]methionine for the last 14 h of culture. The proteins expressed in control and retinoic acid-treated cells were identified by microsequencing after "in-gel" tryptic digestion of the spot or by immunodetection with specific antibodies after two-dimensional gel blotting. Intracellular protein modifications included one of 56.9 kDa and with an isoelectric point (pI) of 5.8 whose synthesis was previously reported to be up-regulated by 75%. Microsequencing of two internal peptides did not reveal a known protein. Changes to the chondrocyte phenotype were also recorded in the culture medium, as a decrease in type II collagen synthesis and expression of the small proteoglycan, decorin. Several new spots were also observed after treatment with retinoic acid, including a large, diffuse spot, not yet characterized, with a mean molecular mass of 39 kDa and a pI of 4.5-5.0. Under our experimental conditions, retinoic acid induces morphological changes of the chondrocytes and dramatic changes in the synthesis of several intracellular and secreted proteins that predate the synthesis of collagen type I (the classical marker of chondrocyte dedifferentiation).

Amino Acid Sequence↗

PubMed1998

Polymerase chain reaction-mediated typing of microorganisms: tracking dissemination of genes and genomes.

The polymerase chain reaction (PCR) is a powerful molecular biology tool which can be used for the identification of species and strains of diverse microorganisms. By aimed amplification of characteristic genes (i.e., genes encoding ribosomal RNA molecules) and subsequent genetic analysis of amplified fragments, information on microbiological systematics and phylogeny can be obtained in a fast and efficient manner. Similar types of gene identification can be used to verify or detect genes responsible for phenotypic characteristics, whereas modified forms of the PCR enable whole genome searches for genetic polymorphisms among strains of a given species. In medical sciences, both strategies, gene and genome variability analysis by PCR, have an increasing impact on the study of the spread of especially those microbes that are multiply resistant to clinically used antibiotics. In this communication we will exemplify the usefulness of PCR-mediated typing of microorganisms from a clinical perspective while focusing on gene- versus genome-scanning. Special emphasis will be placed on analysis of the dissemination and characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains and bacterial factors providing resistance to penicillin and other beta-lactam antibiotics. Technical limitations and possibilities for improvement will be discussed.

Bacterial Typing Techniques↗

PubMed1992

Induction of growth suppression and modification of gene expression in multi-drug-resistant human glioblastoma multiforme cells by recombinant human fibroblast and immune interferon.

The combination of recombinant human fibroblast (IFN-beta) and immune (IFN-gamma) interferon induces enhanced growth suppression and modifies the antigenic phenotype in parental and multi-drug-resistant (MDR) human glioblastoma multiforme (GBM) cells. The present study was conducted to explore the mechanism underlying this cooperative interaction between interferons in inducing growth suppression in MDR-GBM cells. For this analysis we have utilized 2 MDR-GBM cell lines which display a differential sensitivity to growth suppression when exposed to IFN-beta or IFN-gamma. GBM-18-B3 (MDR) cells are more sensitive to growth inhibition by IFN-gamma than by IFN-beta, whereas GBM-18-A3 (MDR) cells are inhibited to a greater degree by IFN-beta than by IFN-gamma. In both cell types, however, growth is suppressed to a greater degree by the combination of interferons than by equivalent concentrations of either type of interferon used alone. Growth suppression induced by the interferons, alone or in combination, was not associated with comparable changes in the steady-state level of MDRI mRNA. In addition, the anti-proliferative effect of interferon was similar in GBM-18 (MDR) cells grown in the presence or absence of colchicine. GBM-18-A3 and GBM-18-B3 cells differed in their de novo and interferon-inducible expression levels of IFN-beta-responsive genes, isg-15 and isg-54. In contrast, both cell types responded in a similar manner with respect to expression of the IFN-gamma-responsive gene, HLA Class II (HLA-DR beta), and HLA Class I, fibronectin and ICAM-I. No further increase in expression of any of the genes was observed which was unique to the combination of interferons.

Cell Division↗

PubMed2003

Loss of pro-apoptotic BH3-only Bcl-2 family member Bim does not protect mutant Lurcher mice from neurodegeneration.

Lurcher (lc) mice have a semi-dominant mutation in the gene encoding the delta2 glutamate receptor (GRID2). The resulting constitutive activity of this receptor in heterozygous +/lc (grid(+/lc)) and homozygous (grid(lc/lc)) mice leads to the death of all cerebellar Purkinje cells and most afferent granule neurons. Some studies have indicated that the death of Purkinje cells occurs by apoptosis, and the secondary loss of granule neurons has been shown to require the pro-apoptotic Bcl-2 family member Bax. The BH3-only protein Bim has been shown to contribute to cytokine withdrawal-induced apoptosis of sympathetic neurons and to be responsible for the kidney degeneration in mice lacking the pro-survival protein Bcl-2. Because Bim is expressed strongly in cerebellar Purkinje cells, we have examined whether it has a role in their death in mutant Lurcher mice. Our studies show that Bim deficiency does not modify the Lurcher phenotype, ruling out an indispensable role for Bim in this neurodegenerative disease.

Animals↗