Biomedical subjects

A F Parlow

Publications and source records attributed to A F Parlow.

At least 55 records · Page 3Linked to original sources

PubMed2001

Disruption of differentiated functions during viral infection in vivo. V. Mapping of a locus involved in susceptibility of mice to growth hormone deficiency due to persistent lymphocytic choriomeningitis virus infection.

Lymphocytic choriomeningitis virus (LCMV) Armstrong strain selectively and persistently infects the majority of growth hormone (GH) producing cells in the anterior lobe of pituitary glands of C3H/St mice but negligibly infects GH producing cells of BALB/WEHI mice (Oldstone et al., Virology 142, 175--182, 1985; Oldstone et al., Science 218, 1125--1127, 1982). Although infected GH cells remain free of structural damage, disrupted initiation of GH transcription (Klavinskis and Oldstone, J. Gen. Virol. 68, 1867--1873, 1989; Valsamakis et al., Virology 156, 214--220, 1987) occurs with a resultant decrease in the synthesis of GH, leading to a failure of growth and development (Oldstone et al., Science 218, 1125--1127, 1982). Microsatellite mapping of DNA obtained from 101 individual C3H/St x BALB/WEHI F1 x F1 mice shows that the growth failure correlates with host genes linked (P value 0.0008) on chromosome 17 just outside of the H-2D MHC site between D17 Mit24 and D17 Mit51, a distance of 2.5 cM. The genetic mapping done here excludes alpha-dystroglycan (alpha-DG), a known receptor for LCMV (Cao et al., Science 282, 2079--2081, 1998) in pathogenesis of GH disease, as alpha-DG is encoded in the mouse by a gene residing on chromosome 9 (Yotsumoto et al., Hum. Mol. Genet. 5, 1259--1267, 1996).

Animals↗

PubMed2001

Hypomorphic phenotype in mice with pituitary-specific knockout of steroidogenic factor 1.

The bacteriophage Cre recombinase provides a powerful approach for tissue-specific gene inactivation. Using a Cre transgene driven by the common alpha subunit of glycoprotein hormones (alphaGSU-Cre), we have previously inactivated steroidogenic factor 1 (SF-1) in the anterior pituitary, causing hypogonadotropic hypogonadism with sexual infantilism, sterility, and severe gonadal hypoplasia. We now explore the molecular mechanisms underlying a hypomorphic gonadal phenotype in mice carrying two floxed SF-1 alleles (F/F) relative to mice carrying one recombined and one floxed allele (F/R). Because their Cre-mediated disruption of the locus encoding SF-1 was less efficient, alphaGSU-Cre, F/F mice retained some gonadotropin-expressing cells in the anterior pituitary, thereby stimulating some gonadal function. This novel in vivo model for exploring the effects of differing levels of gonadotropins on gonadal development highlights the need for careful genotype-phenotype comparisons in studies using Cre recombinase to produce tissue-specific knockouts.

Animals↗

PubMed2001

Ovarian expression of human insulin-like growth factor-I in transgenic mice results in cyst formation.

Insulin-like growth factor-I (IGF-I) has been implicated in a wide variety of physiological processes including ovarian function. To better understand the ovarian role of IGF-I, transgenic mice harbouring a human IGF-I cDNA (hIGF-I) under the control of the mouse LH receptor promoter were generated. Expression of the hIGF-I, determined by Northern blot, was found to occur in the gonad tissues of these transgenic mice. The hIGF-I protein was also detectable by radioimmunoassay in ovarian extracts as well as in the plasma. The fertility of mating transgenic females, as estimated by the number of implantation sites post-coitum, did not appear to be affected. However, transgenic females who failed to mate and produce offspring were found to possess polycystic ovaries. Evaluation of testosterone, estradiol, and LH levels revealed that transgenic animals had significantly elevated circulating levels of testosterone compared to their non-transgenic littermates, while LH levels in transgenic females were significantly lower. Yet, estradiol appeared to be unaffected. These results support the contention that the IGF system plays an important role in ovarian function and that an imbalance in this system may result in ovarian pathology.

Animals↗

PubMed2001

Huntingtin interacting protein 1 Is a clathrin coat binding protein required for differentiation of late spermatogenic progenitors.

Huntingtin-interacting protein 1 (HIP1) interacts with huntingtin, the protein whose gene is mutated in Huntington's disease. In addition, a fusion between HIP1 and platelet-derived growth factor beta receptor causes chronic myelomonocytic leukemia. The HIP1 proteins, including HIP1 and HIP1-related (HIP1r), have an N-terminal polyphosphoinositide-interacting epsin N-terminal homology, domain, which is found in proteins involved in clathrin-mediated endocytosis. HIP1 and HIP1r also share a central leucine zipper and an actin binding TALIN homology domain. Here we show that HIP1, like HIP1r, colocalizes with clathrin coat components. We also show that HIP1 physically associates with clathrin and AP-2, the major components of the clathrin coat. To further understand the putative biological role(s) of HIP1, we have generated a targeted deletion of murine HIP1. HIP1(-/-) mice developed into adulthood, did not develop overt neurologic symptoms in the first year of life, and had normal peripheral blood counts. However, HIP1-deficient mice exhibited testicular degeneration with increased apoptosis of postmeiotic spermatids. Postmeiotic spermatids are the only cells of the seminiferous tubules that express HIP1. These findings indicate that HIP1 is required for differentiation, proliferation, and/or survival of spermatogenic progenitors. The association of HIP1 with clathrin coats and the requirement of HIP1 for progenitor survival suggest a role for HIP1 in the regulation of endocytosis.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Somatostatin is required for masculinization of growth hormone-regulated hepatic gene expression but not of somatic growth.

Pulsatile growth hormone (GH) secretion differs between males and females and regulates the sex-specific expression of cytochrome P450s in liver. Sex steroids influence the secretory dynamics of GH, but the neuroendocrine mechanisms have not been conclusively established. Because periventricular hypothalamic somatostatin (SST) expression is greater in males than in females, we generated knockout (Smst(-/-)) mice to investigate whether SST peptides are necessary for sexually differentiated GH secretion and action. Despite marked increases in nadir and median plasma GH levels in both sexes of Smst(-/-) compared with Smst(+/+) mice, the mutant mice had growth curves identical to their sibling controls and retained a normal sexual dimorphism in weight and length. In contrast, the liver of male Smst(-/-) mice was feminized, resulting in an identical profile of GH-regulated hepatic mRNAs between male and female mutants. Male Smst(-/-) mice show higher expression of two SST receptors in the hypothalamus and pituitary than do females. These data indicate that SST is required to masculinize the ultradian GH rhythm by suppressing interpulse GH levels. In the absence of SST, male and female mice exhibit similarly altered plasma GH profiles that eliminate sexually dimorphic liver function but do not affect dimorphic growth.

Animals↗

PubMed2001

Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4.

The type 2 deiodinase (D2), a selenoenzyme that catalyzes the conversion of T4 to T3 via 5'-deiodination, is expressed in the pituitary, brain, brown adipose tissue (BAT), and the reproductive tract. To examine the physiological role of this enzyme, a mouse strain lacking D2 activity was developed using homologous recombination. The targeting vector contained the Neo gene in place of a 2.6-kb segment of the Dio2 gene. This segment comprises 72% of the coding region and includes the TGA codon that codes for the selenocysteine located at the active site of the enzyme. Mice homologous for the targeted deletion [D2 knockout (D2KO)] had no gross phenotypic abnormalities, and development and reproductive function appeared normal, except for mild growth retardation (9%) in males. No D2 activity was observed in any tissue in D2KO mice under basal conditions, or under those that normally induce this enzyme such as cold-exposure (BAT) or hypothyroidism (brain, BAT, and pituitary gland). Furthermore, no D2 activity was present in cultured astrocytes, nor could it be induced by treatment of the cells with forskolin. Although D2 mRNA transcripts were detected in BAT RNA obtained from cold-exposed wild-type (WT) mice, none was detected in BAT RNA from comparably-treated D2KO mice. Levels of D1 in the liver, thyroid, and pituitary were the same in WT and D2KO animals, whereas D3 activity in D2KO cerebrum was twice that in WT cerebrum. Serum T3 levels were comparable in adult WT and D2KO mice. However, serum T4 and TSH levels were both elevated significantly (40% and 100%, respectively) in the D2KO mice, suggesting that the pituitary gland of the D2KO mouse is resistant to the feedback effect of plasma T4. This view was substantiated by the finding that serum TSH levels in hypothyroid WT mice were suppressed by administration of either T4 or T3, but only T3 was effective in the D2KO mouse. The data also suggest that the clearance of T4 from plasma was reduced in the D2KO mouse. In summary, targeted inactivation of the selenodeiodinase Dio2 gene results in the complete loss of D2 activity in all tissues examined. The increased serum levels of T4 and TSH observed in D2KO animals demonstrate that the D2 is of critical importance in the feedback regulation of TSH secretion.

Adipose Tissue, Brown↗

PubMed2001

Steroidogenic factor 1 (SF1) is essential for pituitary gonadotrope function.

Knockout mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF1) exhibit a complex endocrine phenotype that includes adrenal and gonadal agenesis, impaired expression of pituitary gonadotropins, and absence of the ventromedial hypothalamic nucleus (VMH). These multiple defects complicate efforts to delineate primary versus secondary effects of SF1 deficiency in different tissues, such that its direct role in gonadotropes remains uncertain. To define this role, we have expressed Cre recombinase driven by the promoter region of the common alpha subunit of glycoprotein hormones (alpha GSU), thereby inactivating a loxP-modified SF1 locus in the anterior pituitary gland. Although pituitary-specific SF1 knockout mice were fully viable, they were sterile and failed to develop normal secondary sexual characteristics. Their adrenal glands and VMH appeared normal histologically, but their testes and ovaries were severely hypoplastic. alpha GSU-Cre, loxP mice had normal levels of most pituitary hormones, but had markedly decreased expression of LH and FSH. Treatment with exogenous gonadotropins stimulated gonadal steroidogenesis, inducing germ cell maturation in males and follicular and uterine maturation in females--establishing that the gonads can respond to gonadotropins. The pituitary-specific SF1 knockout mice are a novel genetic model of hypogonadotropic hypogonadism that establishes essential role(s) of SF1 in pituitary gonadotropes.

Animals↗

PubMed2001

Hormonal regulation of tight junction closure in the mouse mammary epithelium during the transition from pregnancy to lactation.

Closure of the tight junctions of the mammary epithelium has been shown to accompany the onset of copious milk secretion or lactogenesis, stage 2, in both goats and humans. Here we use injection of [(14)C]sucrose and FITC-albumin (fluorescein isothiocyanate-albumin) into the mammary duct to follow the course of tight junction closure during lactogenesis in mice. To examine the hormonal changes responsible, we ovariectomized day 16 or 17 pregnant mice and found that closure followed ovariectomy with a mean delay of 13.6+/-1.5 (s.e.m. ) h. That progesterone withdrawal is the trigger for closure was shown by the finding that injection of progesterone within 4 h of ovariectomy delayed closure and that closure occurred after injection of the progesterone antagonist RU 486 in intact late pregnant mice. Endocrine ablation studies showed that low to moderate concentrations of corticosterone and either placental lactogen or prolactin are necessary for tight junction closure triggered by progesterone withdrawal. Thus the hormonal requirements for tight junction closure are similar to those shown by other investigators to promote lactogenesis, stage 2. Further, the tight temporal control of tight junction permeability suggests that ovariectomy of the late pregnant mouse may be a good model for molecular studies of the lactogenic switch.

Animals↗

PubMed2001

Cyclosporine A-induced mammary hyperplasia and hyperprolactinemia in New Zealand White rabbits.

PURPOSE: To investigate the potential activity of cyclosporin A (CsA) to induce mammary hyperplasia in New Zealand White (NZW) rabbits. METHODS: Female NZW rabbits were used throughout experiments. To simulate the conditions of immunosuppression, CsA (10 mg/kg of body weight/d) was administered intravenously on a daily basis for 14 days and methylprednisolone (5 mg/kg/d) was administered on the first two days. The CsA (10 mg/kg/d) also was administered without methylprednisolone for 14 days to another cohort of rabbits. Mammary tissue of each rabbit was palpated and serially measured during this treatment period. The CsA was discontinued, and rabbits were monitored for 14 more days during the washout period. Sequential plasma concentrations of prolactin, 17beta-estradiol, and progesterone in each blood sample were determined by use of radioimmunoassay. RESULTS: All NZW rabbits treated with CsA and methylprednisolone for immunosuppression consistently developed striking mammary tissue hyperplasia. At the end of treatment with CsA and methylprednisolone, mammary glands had extensive changes consistent with actively lactating glands. Similar but less extensive hyperplasia developed in response to CsA alone. Plasma concentration of prolactin increased during treatment and decreased during the washout period. Plasma concentration of 17beta-estradiol increased during treatment and continued to increase during the washout period. Plasma progesterone concentration decreased at the end of treatment. On discontinuation of CsA, mammary hyperplasia regressed. CONCLUSIONS: Cyclosporine A, with or without methylprednisolone, induces mammary hyperplasia and hyperprolactinemia in NZW rabbits. This rabbit model may be a reliable in vivo system by which to study immunosuppressant-induced structural and functional changes of mammary glands similar to those observed in humans.

Animals↗

PubMed2000

The human ARHI tumor suppressor gene inhibits lactation and growth in transgenic mice.

ARHI is a novel imprinted tumor suppressor gene. To study its function in vivo, we have developed transgenic mice that overexpress ARHI. Offspring bearing the transgene had significantly lower body weights than did nontransgenic littermates. In addition, strong expression of the ARHI transgene was associated with greatly impaired mammary gland development and lactation, failure of ovarian folliculogenesis resulting in decreased fertility, loss of neurons in the cerebellar cortex, and impaired development of the thymus. Decrease in body size and defects in the mammary glands correlated with the level of transgene expression. Immunohistochemical analysis indicated that expression of prolactin (PRL), but not growth hormone, was lower in the pituitary glands of mice with defective mammary gland development. The defect in pregnancy-associated mammary tissue proliferation was associated with decreased serum PRL and progesterone levels. Moreover, lower levels of estrogen receptor and progesterone receptor were observed in postpartum mammary glands and in the ovaries of mice that overexpressed ARHI. Our data suggest that ARHI can inhibit PRL secretion and act as a negative regulator in murine growth and development.

Animals↗

PubMed2000

Pharmacological evidence that prolactin acts from late gestation to promote maternal behaviour in rabbits.

We investigated the role of prolactin and suckling stimulation in the expression of maternal behaviour of primiparous rabbits. Bromocriptine (1 mg/kg/day), given to intact mothers across postpartum days 1-5, decreased serum concentrations of prolactin to undetectable levels, reduced crouching, and increased time inside the nest. Failure of maternal nest-building, provoked by bromocriptine injections from pregnancy day 26 to parturition or to postpartum day 5, correlated with a stronger reduction in crouching and an increased time inside the nest, measures of disturbed maternal behaviour, on postpartum days 3 and 5. Preventing suckling by thelectomy did not prevent prolactin release but reduced crouching incidence and increased the time spent inside the nest on postpartum days 3 and 5. Bromocriptine, injected in thelectomized mothers across postpartum days 1-5, further reduced the incidence of crouching and increased the time spent inside the nest on postpartum days 3 and 5. We conclude that prolactin acting prepartum facilitates maternal behaviour initiation in rabbits and, together with pup stimulation, maintains this behaviour across lactation.

Animals↗

PubMed2000

The similarity of FSH-releasing factor to lamprey gonadotropin-releasing hormone III (l-GnRH-III).

To validate further the existence of a specific hypothalamic follicle stimulating hormone releasing factor (FSHRF), stalk-median eminence (SME) fragments from sheep and whole hypothalami from male rats were purified by gel filtration on Sephadex G-25, and the gonadotropin-releasing activity on hemipituitaries of rats incubated in vitro was determined by bioassay and compared with the radioimmunoassayable luteinizing hormone releasing hormone (LHRH) and lamprey gonadotropin releasing hormone (l-GnRH) activities in the fractions. The FSH-releasing fractions eluted in the same sequence of tubes from the Sephadex column found earlier by in vivo bioassay and were clearly separated from the immunoassayable and bioassayable LHRH. The radioimmunoassay (RIA) for l-GnRH recognized equally l-GnRH-I and -III but had negligible cross-reactivity with LHRH. Fractionation of rat hypothalamic extract by gel filtration on Sephadex G-25 revealed three peaks of l-GnRH determined by RIA, all of which eluted prior to the peak of LHRH. Only the second peak had FSH-releasing but not LH-releasing activity. To determine if this FSH-releasing activity was caused by the presence of l-GnRH in the fraction, the pituitaries were incubated with normal rabbit serum or the l-GnRH antiserum (1:1000), and the effect on the FSH- and LH-releasing activity of the FSH-releasing fraction and the LH-releasing activity of LHRH was determined. The antiserum had no effect on basal release of either FSH or LH but eliminated the FSH-releasing activity of the active fraction without altering the LH-releasing activity of LHRH. Since l-GnRH-I has little activity to release FSH or LH, and its activity is nonselective, whereas previous experiments have shown that l-GnRH-III highly selectively releases FSH with a potency equal to that of LHRH to release LH, the results support the hypothesis that the FSH-releasing activity observed in these experiments was caused by l-GnRH-III or a closely related peptide.

Animals↗

PubMed2000

The possible role of prolactin in the circadian rhythm of leptin secretion in male rats.

In humans there is a circadian rhythm of leptin concentrations in plasma with a minimum in the early morning and a maximum in the middle of the night. By taking blood samples from adult male rats every 3 hr for 24 hr, we determined that a circadian rhythm of plasma leptin concentrations also occurs in the rat with a peak at 0130h and a minimum at 0730h. To determine if this rhythm is controlled by nocturnally released hormones, we evaluated the effect of hormones known to be released at night in humans, some of which are also known to be released at night in rats. In humans, prolactin (PRL), growth hormone (GH), and melatonin are known to be released at night, and adrenocorticotropic hormone (ACTH) release is inhibited. In these experiments, conscious rats were injected intravenously with 0.5 ml diluent or the substance to be evaluated just after removal of the first blood sample (0.3 ml), and additional blood samples (0.3 ml) were drawn every 10 min thereafter for 2 hr. The injection of highly purified sheep PRL (500 microg) produced a rapid increase in plasma leptin that persisted for the duration of the experiment. Lower doses were ineffective. To determine the effect of blockade of PRL secretion on leptin secretion, alpha bromoergocryptine (1.5 mg), a dopamine-2-receptor agonist that rapidly inhibits PRL release, was injected. It produced a rapid decline in plasma leptin within 10 min, and the decline persisted for 120 min. The minimal effective dose of GH to lower plasma leptin was 1 mg/rat. Insulin-like growth factor (IGF-1) (10 microg), but not IGF-2 (10 microg), also significantly decreased plasma leptin. Melatonin, known to be nocturnally released in humans and rats, was injected at a dose of 1 mg/rat during daytime (1100h) or nighttime (2300h). It did not alter leptin release significantly. Dexamethasone (DEX), a potent glucocorticoid, was ineffective at a 0. 1-mg dose but produced a delayed, significant increase in leptin, manifest 100-120 min after injection of a 1 mg dose. Since glucocorticoids decrease at night in humans at the time of the maximum plasma concentrations of leptin, we hypothesize that this increase in leptin from a relatively high dose of DEX would mimic the response to the release of corticosterone following stress in the rat and that glucocorticoids are not responsible for the circadian rhythm of leptin concentration. Therefore, we conclude that an increase in PRL secretion during the night may be responsible, at least in part, for the nocturnal elevation of leptin concentrations observed in rats and humans.

Animals↗

PubMed2000

Mechanism of the alcohol cyclic pattern: role of the hypothalamic-pituitary-thyroid axis.

The cause of the cycle of urinary alcohol levels (UALs) in rats fed ethanol continually at a fixed rate is unknown. Rats were fed ethanol intragastrically at a constant dose for 2 mo, and daily body temperatures and UALs were recorded. Body temperature cycled inversely to UAL, suggesting that the rate of metabolism could be mechanistically involved in the rate of ethanol elimination during the cycle. To document this, whole body O(2) consumption rate was monitored daily during the cycle. The rate of O(2) consumption correlated positively with the change in body temperature and negatively with the change in UAL. Since the metabolic rate responds to changes in body temperature, thyroid hormone levels were measured during the UAL cycle. T(4) levels correlated positively with the O(2) consumption rate and negatively with the UALs. In a second experiment using propylthiouracil treatment, UALs did not cycle and a fall in body temperature failed to stimulate an increase in the rate of ethanol elimination. Consequently, rats died of overdose. Likewise, in a third experiment using rats with severed pituitary stalks, UALs failed to cycle and rats died of overdose. From these observations it was concluded that the UAL cycle depends on an intact hypothalamic-pituitary-thyroid axis response to the ethanol-induced drop in body temperature by increasing the rate of ethanol elimination.

Alanine Transaminase↗

PubMed2000

Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism.

Heterozygous disruption of Gnas, the gene encoding the stimulatory G-protein alpha subunit (G(s)alpha), leads to distinct phenotypes depending on whether the maternal (m-/+) or paternal (+/p-) allele is disrupted. G(s)alpha is imprinted, with the maternal allele preferentially expressed in adipose tissue. Hence, expression is decreased in m-/+ mice but normal in +/p- mice. M-/+ mice become obese, with increased lipid per cell in white and brown adipose tissue, whereas +/p- mice are thin, with decreased lipid in adipose tissue. These effects are not due to abnormalities in thyroid hormone status, food intake, or leptin secretion. +/p- mice are hypermetabolic at both ambient temperature (21 degrees C) and thermoneutrality (30 degrees C). In contrast, m-/+ mice are hypometabolic at ambient temperature and eumetabolic at thermoneutrality M-/+ and wild-type mice have similar dose-response curves for metabolic response to a beta(3)-adrenergic agonist, CL316243, indicating normal sensitivity of adipose tissue to sympathetic stimulation. Measurement of urinary catecholamines suggests that +/p- and m-/+ mice have increased and decreased activation of the sympathetic nervous system, respectively. This is to our knowledge the first animal model in which a single genetic defect leads to opposite effects on energy metabolism depending on parental inheritance. This probably results from deficiency of maternal- and paternal-specific Gnas gene products, respectively.

Adrenergic beta-Agonists↗

PubMed2000

Hormonal regulation of radioiodide uptake activity and Na+/I- symporter expression in mammary glands.

The observation that radioiodide uptake (RAIU) activity, mediated by the Na+/I- symporter (NIS), is significantly increased in lactating breast suggests that RAIU and NIS expression in mammary gland are modulated by hormones involved in active lactation. We showed that both the NIS expression level and RAIU in rat mammary gland are maximal during active lactation compared to those in the mammary glands of virgin and pregnant rats as well as the involuting mammary gland. In the lactating mammary gland, NIS is clustered on the basolateral membrane of alveolar cells as a lesser glycosylated form than NIS in thyroid. The RAIU of lactating mammary gland was partially inhibited by treatment with a selective oxytocin antagonist or bromocriptine, an inhibitor of PRL release. These findings suggest that RAIU and NIS expression in mammary gland are at least in part modulated by oxytocin and PRL. Indeed, we showed that NIS messenger ribonucleic acid level was increased in a dose-dependent manner by oxytocin and PRL in histocultured human breast tumors.

Animals↗

PubMed1999

Polarized secretion of transgene products from salivary glands in vivo.

Previously (Kagami et al. Hum. Gene Ther. 1996;7:2177-2184) we have shown that salivary glands are able to secrete a transgene-encoded protein into serum as well as saliva. This result and other published data suggest that salivary glands may be a useful target site for vectors encoding therapeutic proteins for systemic delivery. The aim of the present study was to assess in vivo if transgene-encoded secretory proteins follow distinct, polarized sorting pathways as has been shown to occur "classically" in cell biological studies in vitro. Four first-generation, E1-, type 5 recombinant adenoviruses were used to deliver different transgenes to a rat submandibular cell line in vitro or to rat submandibular glands in vivo. Subsequently, the secretory distribution of the encoded proteins was determined. Luciferase, which has no signal peptide, served as a cell-associated, negative control and was used to correct for any nonspecific secretory protein release from cells. The three remaining transgene products tested, human tissue kallikrein (hK1), human growth hormone (hGH), and human alpha1-antitrypsin (halpha1AT), were predominantly secreted (>96%) in vitro. Most importantly, in vivo, after a parasympathomimetic secretory stimulus, both hK1 and hGH were secreted primarily in an exocrine manner into saliva. Conversely, halpha1AT was predominantly secreted into the bloodstream, i.e., in an endocrine manner. The aggregate results are consistent with the recognition of signals encoded within the transgenes that result in specific patterns of polarized protein secretion from rat submandibular gland cells in vivo.

Adenoviridae↗

PubMed1999

Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction.

The lats gene has been identified as a tumour suppressor in Drosophila melanogaster using mosaic screens. Mosaic flies carrying somatic cells that are mutant for lats develop large tumours in many organs. The human LATS1 homologue rescues embryonic lethality and inhibits tumour growth in lats mutant flies, demonstrating the functional conservation of this gene. Biochemical and genetic analyses have revealed that LATS1 functions as a negative regulator of CDC2 (ref. 3). These data suggest that mammalian LATS1 may have a role in tumorigenesis. To elucidate the function of mammalian LATS1, we have generated Lats1-/- mice. Lats1-/- animals exhibit a lack of mammary gland development, infertility and growth retardation. Accompanying these defects are hyperplastic changes in the pituitary and decreased serum hormone levels. The reproductive hormone defects of Lats1-/- mice are reminiscent of isolated LH-hypogonadotropic hypogonadism and corpus luteum insufficiency in humans. Furthermore, Lats1-/- mice develop soft-tissue sarcomas and ovarian stromal cell tumours and are highly sensitive to carcinogenic treatments. Our data demonstrate a role for Lats1 in mammalian tumorigenesis and specific endocrine dysfunction.

Animals↗