Biomedical subjects

M M Matzuk

Publications and source records attributed to M M Matzuk.

At least 73 records · Page 4Linked to original sources

PubMed1998

Mouse models of ovarian failure.

Ovarian failure leading to infertility can be caused by improper prenatal development of the fetal gonad or disruption of the complex postnatal process of folliculogenesis due to alterations in intragonadal or extragonadal regulation. It is critical to have physiological models that mimic events occurring during human development to understand, treat, and prevent ovarian failure in women. Many workers have chosen the mouse as the mammalian model with which to study ovarian function. This review summarizes several key events in female gonadogenesis and folliculogenesis in mice with specific emphasis on spontaneous or induced mutations yielding mouse models that have female infertility owing to ovarian failure.

Animals↗

PubMed1998

FKBP12 is not required for the modulation of transforming growth factor beta receptor I signaling activity in embryonic fibroblasts and thymocytes.

Transforming growth factor beta (TGF-beta) signals through a heteromeric complex of type I and type II transmembrane serine-threonine kinases. Recent evidence suggests that the immunophilin FKBP12 modulates the activity of the type I receptor, based on data that immunosuppressive drugs that disrupt FKBP12 binding to the type I receptor enhance TGF-beta signaling in mink lung epithelial cells, and overexpression of FKBP12 inhibits type I receptor phosphorylation by the type II receptor. To determine the physiological relevance of the FKBP12-TGF-beta receptor I interaction, we investigated whether disruption of this interaction affects TGF-beta-signaling in primary mouse embryo fibroblasts and thymocytes. We found that the addition of excess drugs had no effect on either TGF-beta-mediated transcriptional responses or growth inhibition. Dose-response curves for TGF-beta-mediated signaling in primary fibroblasts and thymocytes isolated from either wild-type or FKBP12-deficient mice were identical. Taken together, our results indicate that FKBP12 does not play a unique physiological role in TGF-beta signaling in primary fibroblasts and thymocytes.

Activin Receptors, Type I↗

PubMed1997

Math1 is essential for genesis of cerebellar granule neurons.

The cerebellum is essential for fine motor control of movement and posture, and its dysfunction disrupts balance and impairs control of speech, limb and eye movements. The developing cerebellum consists mainly of three types of neuronal cells: granule cells in the external germinal layer, Purkinje cells, and neurons of the deep nuclei. The molecular mechanisms that underlie the specific determination and the differentiation of each of these neuronal subtypes are unknown. Math1, the mouse homologue of the Drosophila gene atonal, encodes a basic helix-loop-helix transcription factor that is specifically expressed in the precursors of the external germinal layer and their derivatives. Here we report that mice lacking Math1 fail to form granule cells and are born with a cerebellum that is devoid of an external germinal layer. To our knowledge, Math1 is the first gene to be shown to be required in vivo for the genesis of granule cells, and hence the predominant neuronal population in the cerebellum.

Animals↗

PubMed1997

Gene targeting approaches to neuroendocrinology: oxytocin, maternal behavior, and affiliation.

Transgenic technology affords exciting new opportunities in the field of behavioral neuroendocrinology. We have extended our research into the behavioral function of oxytocin in maternal and social behavior using two transgenic approaches: (i) targeted deletion of the oxytocin gene in mice and (ii) augmented oxytocin receptor expression in the brain. Mice genetically deficient in oxytocin can mate, give birth, and display normal maternal behavior; however, milk ejection and certain aspects of social behavior are affected. Comparative studies of oxytocin receptors have led to the observation that species differences in social organization are associated with differences in receptor distribution. Specifically, monogamous prairie voles and nonmonogamous, asocial montane voles exhibit different patterns of OT receptor expression in the brain. Transgenic mice have been created with a reporter gene driven by the prairie vole oxytocin receptor gene promoter. Analysis of the expression pattern suggests that it should be possible to manipulate receptor expression in the vole brain in order to examine the effects of receptor distribution on behavior.

Animals↗

PubMed1997

Worldwide frequency of a common genetic variant of luteinizing hormone: an international collaborative research. International Collaborative Research Group.

OBJECTIVE: To determine the worldwide frequency of a common immunological LH variant because of two point mutations in the LH beta-subunit gene (Trp8Arg and Ile15Thr). DESIGN: Cross-sectional study on LH status (variant and wild-type) in serum (or DNA) samples from Finland (Finns and Lapps), Estonia, Poland, Sweden, The Netherlands, United Kingdom, Italy, South Africa (blacks), Thailand, China, Japan, and the United States (Hispanics and blacks). SETTING: Academic research environment. PATIENT(S): Ambulatory adult men and women (n = 2,936) with minor illnesses and no known endocrinological disorders. INTERVENTION: A single blood sample was collected from each subject. MAIN OUTCOME MEASURE(S): The LH status was determined by two immunofluorometric assays using monoclonal antibodies. One (assay 1) only recognizes the wild-type LH, the other (assay 2) recognizes equally variant and wild-type LH. The ratio of assay 1 to assay 2 indicates the LH status: wild-type, > 0.9; heterozygote, 0.2 to 0.9; and homozygote, < 0.15. One population (Lapps) was studied by DNA analysis using polymerase chain reaction and allele-specific oligonucleotide hybridization. RESULT(S): The carrier frequency of the variant LH beta allele varied from 7.1% in U.S. Hispanics to 41.9% in Lapps of northern Finland. The variant LH beta allele tended to be more common in populations from Northern Europe as compared with those from Asia. CONCLUSION(S): The high frequency of the LH beta variant worldwide makes it an important confounding factor when obtaining disproportionately low LH levels with some immunometric assays. The LH variant may contribute to some pathologies of the pituitary-gonadal function.

Adolescent↗

PubMed1997

Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility.

Follicle stimulating hormone (FSH) is a member of the glycoprotein hormone family that includes luteinzing hormone (LH), thyroid stimulating hormone, and chorionic gonadotropin. These heterodimeric hormones share a common alpha subunit and differ in their hormone-specific beta subunit. The biological activity is conferred only by the heterodimers. FSH and LH are synthesized in the same cells of the pituitary, the gonadotrophs. FSH receptors are localized to Sertoli cells of the testes and granulosa cells of the ovary. Minimal data has been accumulated so far involving human mutations in the FSH beta, LH beta, or the gonadotropin receptor genes. There are no known mouse strains with mutations in the FSH beta gene. To generate animal models for human diseases involving the gonadotropin signal transduction pathway, we produced mice deficient in the FSH beta subunit and therefore in FSH using ES cell technology. FSH-deficient females are infertile due to a block in folliculogenesis prior to antral follicle formation. Although FSH was predicted to be necessary for spermatogenesis and Sertoli cell growth in males, FSH-deficient males are fertile despite having small testes. Our findings have important implications for male contraceptive development in humans.

Animals↗

PubMed1997

Role of androgens in testicular tumor development in inhibin-deficient mice.

To understand gonadal tumor development, we have previously created a mouse model in which mice deficient in the inhibins develop gonadal sex cord-stromal tumors with essentially 100% penetrance. These tumors develop as early as 4 weeks of age and cause cancer cachexia-like symptoms and subsequent death in the inhibin-deficient mice. Gonadectomized inhibin-deficient mice eventually develop adrenal cortical tumors with nearly 100% penetrance. These studies have identified inhibin as a novel secreted tumor suppressor protein with specificity for the gonads and adrenal glands. Sex steroids have been implicated to influence gonadal tumor development in humans and mice. To determine the role of androgens in gonadal tumorigenesis in inhibin-deficient male mice, we have used a genetic intercross strategy, breeding inhibin alpha mutant mice with tfm (testicular feminization, a naturally occurring androgen receptor mutant) carrying females to eventually generate compound mutant male mice that lack inhibins and carry the tfm mutation. These compound mutant mice, like inhibin-deficient mice, continue to develop testicular tumors and the accompanying cancer cachexia-like wasting syndrome. Consistent with these findings, elevated levels of activins A and B secreted from the gonadal tumors are seen in the adult compound mutant mice as well as the secondary pathological consequences of these high activin levels in the livers and glandular stomachs. However, in contrast to male mice lacking only inhibin, in which essentially 100% of the testicular tumors are hemorrhagic, 65% of the tumors in these compound mutant male mice are less hemorrhagic, and approximately 50% of the compound mutants live longer than 17 weeks of age (95% of the male mice lacking only inhibin die by 12 weeks). These results suggest that androgens are not required for testicular tumor development in inhibin-deficient mice, but may play a regulatory role in testicular tumor progression.

Activins↗

PubMed1997

Insulin-like growth factor I regulates gonadotropin responsiveness in the murine ovary.

The present study shows that insulin-like growth factor I (IGF-I) and FSH receptor (FSHR) mRNAs are selectively coexpressed in a subset of healthy-appearing follicles in murine ovaries, irrespective of cycle stage. Aromatase gene expression, a prime marker for FSH effect, is found only in IGF-I/FSHR-positive follicles, showing that these are healthy, gonadotropin-responsive follicles. Given the striking coexpression of FSHR and IGF-I, we hypothesized that FSH was responsible for follicular IGF-I expression. We found, however, that granulosa cell IGF-I mRNA levels are not reduced in hypophysectomized (+/-PMSG) or FSH knockout mice, indicating that FSH does not have a major role in regulation of granulosa cell IGF-I gene expression. To test the alternative hypothesis that IGF-I regulates FSHR gene expression, we studied ovaries from IGF-I knockout mice. FSHR mRNA was significantly reduced in ovaries from homozygous IGF-I knockout compared with wild type mice and was restored to control values by exogenous IGF-I treatment. The functional significance of the reduced FSHR gene expression in IGF-I knockout ovaries is suggested by reduced aromatase expression and by the failure of their follicles to develop normally beyond the early antral stage. In fact, IGF-I knockout and FSH knockout ovaries appear very similar in terms of arrested follicular development. In summary, we have shown that IGF-I and FSHR are selectively coexpressed in healthy, growing murine follicles and that FSH does not affect IGF-I expression but that IGF-I augments granulosa cell FSHR expression. These data suggest that ovarian IGF-I expression serves to enhance granulosa cell FSH responsiveness by augmenting FSHR expression.

Animals↗

PubMed1996

Oxytocin is required for nursing but is not essential for parturition or reproductive behavior.

Oxytocin, a neurohypophyseal hormone, has been traditionally considered essential for mammalian reproduction. In addition to uterine contractions during labor and milk ejection during nursing, oxytocin has been implicated in anterior pituitary function, paracrine effects in the testis and ovary and the neural control of maternal and sexual behaviors. To determine the essential role(s) of oxytocin in mammalian reproductive function, mice deficient in oxytocin have been generated using embryonic stem cell technology. A deletion of exon 1 encoding the oxytocin peptide was generated in embryonic stem cells at a high frequency and was successfully transmitted in the germ line. Southern blot analysis of genomic DNA from homozygote offspring and in situ hybridization with an exonic probe 3' of the deletion failed to detect any oxytocin or neurophysin sequences, respectively, confirming that the mutation was a null mutation. Mice lacking oxytocin are both viable and fertile. Males do not have any reproductive behavioral or functional defects in the absence of oxytocin. Similarly, females lacking oxytocin have no obvious deficits in fertility or reproduction, including gestation and parturition. However, although oxytocin-deficient females demonstrate normal maternal behavior, all offspring die shortly after birth because of the dam's inability to nurse. Postpartum injections of oxytocin to the oxytocin deficient mothers restore milk ejection and rescue the offspring. Thus, despite the multiple reproductive activities that have been attributed to oxytocin, oxytocin plays an essential role only in milk ejection in the mouse.

Animals↗

PubMed1996

Genetic analysis of the Müllerian-inhibiting substance signal transduction pathway in mammalian sexual differentiation.

Müllerian-inhibiting substance (MIS) is a member of the transforming growth factor-beta (TGF-beta) gene family. MIS expression in males causes the regression of the Müllerian ducts, an essential process in male sexual differentiation. Recently, an MIS type II receptor gene has been isolated that is expressed during embryogenesis in mesenchymal cells adjacent to the Müllerian duct epithelium and in Sertoli and granulosa cells of the fetal and adult, male and female gonads, respectively. MIS receptor mutant males develop as internal pseudohermaphrodites, possessing a complete male reproductive tract and also a uterus and oviducts, a phenocopy of MIS ligand-deficient male mice. They express both MIS mRNA and protein, showing that ligand was present, but target organs were hormone-insensitive. All produce sperm, but the majority were infertile because the presence of their female reproductive organs blocks sperm transfer into females. Focal seminiferous tubule atrophy accompanied by Leydig cell hyperplasia was observed and began as early as 2 months of age. The phenotype of MIS ligand/MIS receptor double mutant males was indistinguishable from those of each single mutant. MIS receptor/alpha-inhibin double mutant males developed testicular stromal tumors and large fluid-filled uteri that were identical in phenotype to MIS ligand/alpha-inhibin double mutant males. These studies provide in vivo evidence that MIS is the only ligand of the MIS type II receptor, in contrast to the complexity of other TGF-beta gene family signaling pathways.

Alleles↗

PubMed1996

Growth differentiation factor-9 is required during early ovarian folliculogenesis.

Growth factors synthesized by ovarian somatic cells directly affect oocyte growth and function, but it is unclear whether oocyte-secreted factors play a reciprocal role in modulating somatic cell functions in vivo. During the functional analysis of members of the transforming growth factor-beta superfamily in mouse development, we have uncovered a new family member, growth differentiation factor-9 (GDF-9), which is required for ovarian folliculogenesis. GDF-9 messenger RNA is synthesized only in the oocyte from the primary one-layer follicle stage until after ovulation. Here we analyse ovaries from GDF-9-deficient female mice and demonstrate that primordial and primary one-layer follicles can be formed, but there is a block in follicular development beyond the primary one-layer follicle stage which leads to complete infertility. Oocyte growth and zona pellucida formation proceed normally, but other aspects of oocyte differentiation are compromised. Thus, GDF-9 is the first oocyte-derived growth factor required for somatic cell function in vivo.

Animals↗

PubMed1996

Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice.

Manganese superoxide dismutase (SOD2) converts superoxide to oxygen plus hydrogen peroxide and serves as the primary defense against mitochondrial superoxide. Impaired SOD2 activity in humans has been associated with several chronic diseases, including ovarian cancer and type I diabetes, and SOD2 overexpression appears to suppress malignancy in cultured cells. We have produced a line of SOD2 knockout mice (SOD2m1BCM/SOD2m1BCM) that survive up to 3 weeks of age and exhibit several novel pathologic phenotypes including severe anemia, degeneration of neurons in the basal ganglia and brainstem, and progressive motor disturbances characterized by weakness, rapid fatigue, and circling behavior. In addition, SOD2m1BCM/SOD2m1BCM mice older than 7 days exhibit extensive mitochondrial injury within degenerating neurons and cardiac myocytes. Approximately 10% of SOD2m1BCM/SOD2m1BCM mice exhibit markedly enlarged and dilated hearts. These observations indicate that SOD2 deficiency causes increased susceptibility to oxidative mitochondrial injury in central nervous system neurons, cardiac myocytes, and other metabolically active tissues after postnatal exposure to ambient oxygen concentrations. Our SOD2-deficient mice differ from a recently described model in which homozygotes die within the first 5 days of life with severe cardiomyopathy and do not exhibit motor disturbances, central nervous system injury, or ultrastructural evidence of mitochondrial injury.

Animals↗

PubMed1996

Growth retardation and cysteine deficiency in gamma-glutamyl transpeptidase-deficient mice.

gamma-Glutamyl transpeptidase (GGT) is an ectoenzyme that catalyzes the first step in the cleavage of glutathione (GSH) and plays an essential role in the metabolism of GSH and GSH conjugates of carcinogens, toxins, and eicosanoids. To learn more about the role of GGT in metabolism in vivo, we used embryonic stem cell technology to generate GGT-deficient (GGTm1/GGTm1) mice. GGT-deficient mice appear normal at birth but grow slowly and by 6 weeks are about half the weight of wild-type mice. They are sexually immature, develop cataracts, and have coats with a gray cast. Most die between 10 and 18 weeks. Plasma and urine GSH levels in the GGTm1/GGTm1 mice are elevated 6-fold and 2500-fold, respectively, compared with wild-type mice. Tissue GSH levels are markedly reduced in eye, liver, and pancreas. Plasma cyst(e)ine levels in GGTm1/GGTm1 mice are reduced to approximately 20% of wild-type mice. Oral administration of N-acetylcysteine to GGTm1/GGTm1 mice results in normal growth rates and partially restores the normal agouti coat color. These findings demonstrate the importance of GGT and the gamma-glutamyl cycle in cysteine and GSH homeostasis.

Animals↗

PubMed1996

Structural analysis of the mouse activin beta C gene.

Using a mouse activin beta C cDNA probe, we have cloned over 38 kb of genomic DNA encompassing the mouse activin beta C gene. Mouse activin beta C is encoded by 2 exons separated by a large 12.1 kb intron. Exon 1 encodes the 17 amino acid signal peptide and 88 amino acids of the propeptide. Exon 2 encodes the remaining 130 amino acids of the propeptide and the entire 117 amino acid mature peptide. Unlike the activin beta A and beta B expression patterns, Northern blot analysis of adult mouse tissues shows that the activin beta C mRNA is expressed only in the liver as a major species of approximately 2.1 kb. The liver-specific expression of activin beta C suggests an important role of dimeric activin beta C in normal liver function. These studies allow us to address the function of activin beta C in mammalian development.

Activins↗

PubMed1996

Tissue-specific binding of radiolabeled activin A by activin receptors and follistatin in postimplantation rat and mouse embryos.

Activin affects the growth and differentiation of many cultured cell types, including rat anterior pituitary cells and gonadal and neuronal cell lines. Endogenous activins regulate mesoderm induction, body axis formation, and organogenisis in the developing embryo. The messenger RNAs encoding inhibin/activin subunits, follistatin (an activin-binding protein), and activin type II receptors (ActRII and IIB) are expressed in various cell types and tissues of the embryonic rat and mouse. Follistatin-deficient mice have numerous embryonic defects, including shiny taut skin, allowing relatively easy identification by the later stages of embryogenesis. ActRII-deficient mice, on the other hand, show limited developmental defects, with some (22%) embryonic day 18.5 (E18.5) ActRII-deficient embryos showing various skeletal and facial abnormalities. The present study was undertaken to identify the target tissues for biologically active activin A and assess the significance of its association with ActRII and follistatin in developing rat and mouse embryos. Fresh-frozen, slide-mounted, rat (E13 to E19) and mouse (E18.5) embryo sections were incubated with 125I-labeled recombinant human activin A. Nonspecific binding was evaluated by competition with an excess of cold activin A. As determined by image analysis, the highest levels of activin A binding were observed throughout the brain, spinal cord, and trigeminal and spinal ganglia at all ages. Lower levels of binding were found in the dermis of the skin starting on E15. Follistatin-deficient mice demonstrated similar patterns and levels of activin A binding in the neural tissues compared to wild-type controls, but binding was absent in the skin. In ActRII-deficient mice, activin A binding was completely absent in neural tissues, but was similar to wild-type control levels in the dermal layer of the skin. The data indicate that activin A binds to specific tissues of mouse and rat embryos and that binding is dependent upon the presence of ActRII in the central and peripheral nervous system and on follistatin in the skin.

Activin Receptors↗

PubMed1996

Gonadotropins are essential modifier factors for gonadal tumor development in inhibin-deficient mice.

We previously demonstrated that mice deficient in inhibin develop gonadal sex cord-stromal tumors with nearly 100% penetrance. These ovarian and testicular tumors develop as early as 4 weeks of age and eventually cause cachexia-like symptoms and death in the inhibin-deficient mice. Gonadectomized inhibin-deficient mice initially do not develop this wasting syndrome, but eventually will develop adrenal cortical tumors with similar penetrance. These studies have demonstrated that inhibin is a secreted type of tumor suppressor in the gonads and adrenal glands. Gonadotropins are implicated to influence gonadal tumor development in humans as well as experimental animals, and in inhibin-deficient mice, serum FSH levels are elevated. To determine whether gonadotropins influence the development and/or progression of the tumors in the inhibin-deficient mice, we took advantage of a naturally occurring mutant mouse, hypogonadal (hpg); hpg/hpg mice lack a functional GnRH gene and, therefore, have suppressed FSH and LH levels. Heterozygous hpg/+mice were crossed to heterozygous inhibin mutant mice to generate compound homozygous mutant mice that lack both inhibin and GnRH. These compound homozygous mutant mice do not develop a wasting syndrome, do not exhibit gonadal or adrenal tumors, and can survive for more than 1 yr. These results demonstrate that gonadotropins are essential modifier factors for tumor development in inhibin-deficient mice.

Animals↗

PubMed1996

Activin signaling through activin receptor type II causes the cachexia-like symptoms in inhibin-deficient mice.

Activins and inhibins, members of the transforming growth factor-beta superfamily, are involved in diverse physiological and developmental processes. We have previously shown that mice deficient in alpha-inhibin develop gonadal sex cord-stromal tumors at an early age. The tumor development is rapidly followed by a wasting syndrome that includes severe weight loss, hepatocellular necrosis around the central vein, and depletion of the parietal cells in the glandular stomach. The liver histology in inhibin-deficient mice is similar to the pathological effects of short-term treatment of rats and mice with recombinant activin A. Consistent with these findings, we have shown that the gonadal tumors in the inhibin-deficient mice secrete high levels of activins. In addition, Northern blot analysis has localized activin receptor type II (ActRII) to the liver. Based on these studies, we postulated that tumor-produced activins act through ActRII to cause the wasting syndrome in inhibin-deficient mice. To test this hypothesis and determine the significance of elevated levels of activin signaling through ActRII in vivo, we generated compound homozygous mutant mice deficient in both alpha-inhibin and ActRII. Despite the continued development of gonadal sex cord-stromal tumors and elevated serum levels of activin A and B, the compound homozygous mutant mice suffered no unusual weight loss, and the stomachs and livers of the majority of the mice were histologically normal. These results demonstrate that increased levels of activin signaling through ActRII in hepatocytes and the glandular stomach causes the hepatocellular necrosis and depletion of parietal cells in the glandular stomach as well as the severe weight loss in vivo.

Activin Receptors↗

PubMed1996

Transgenic mice in the analysis of reproductive development and function.

Transgenic mice have become important model systems for studying molecular, cellular, organ, and whole animal physiology. In particular, transgenic technology allows determination of cell lineage differentiation and the role(s) of specific proteins in mammalian development and oncogenesis. Transgenic mice can be created that express wild-type genes, mutant genes, marker genes or cell lethal genes in a tissue-specific manner. In addition, homologous recombination strategies in embryonic stem cells permit more sophisticated manipulation of the mammalian genome, including the functional deletion of specific genes in whole mice or in a specific tissue. Since all transgenic mice created must be bred to study the consequences of transgene or mutant allele expression, a number of effects of these genome manipulations on the reproductive development and function of these mice have been uncovered. In this review, we summarize the transgenic mouse models in which defects and abnormalities in the reproductive axis have been demonstrated.

Animals↗