Loss of Sexually Dimorphic Liver Gene Expression upon Hepatocyte-Specific Deletion of Stat5a-Stat5b Locus

Hepatocyte-specific, albumin-Cre recombinase-mediated deletion of the entire mouse Stat5a-Stat5b locus was carried out to evaluate the role of signal transducer and activator of transcription 5a and 5b (STAT5ab) in the sex-dependent transcriptional actions of GH in the liver. The resultant hepatocyte STAT5ab-deficient mice were fertile, and unlike global STAT5b-deficient male mice, postnatal body weight gain was normal, despite a 50% decrease in serum IGF-I. Whole-liver STAT5ab RNA decreased by approximately 65–85%, and residual STAT5 immunostaining was observed in a minority of the hepatocytes, indicating incomplete excision by Cre-recombinase. Quantitative PCR analysis of 20 sexually dimorphic, liver-expressed genes revealed significant down-regulation of 10 of 11 male-specific genes in livers of male hepatocyte STAT5ab-deficient mice. Class I female-specific liver genes were markedly up-regulated (de-repressed), whereas the expression of class II female genes, belonging to the Cyp3a subfamily, was unaffected by the loss of hepatocyte STAT5ab. STAT5ab is thus required in the liver for positive regulation of male-specific genes and for negative regulation of a subset of female-specific genes. Continuous GH infusion strongly induced (>500-fold) the class II female gene Cyp3a16 in both wild-type and hepatocyte STAT5ab-deficient male mice, indicating sex-specific transcriptional regulation by GH that is STAT5ab independent. In contrast, hepatocyte STAT5ab deficiency abolished the strong suppression of the male-specific Cyp2d9 by continuous GH seen in control mouse liver. Analysis of global STAT5a-deficient mice indicated no essential requirement of STAT5a for expression of these sex-specific liver Cyp genes. Thus, the major loss of liver sexual dimorphism in hepatocyte STAT5ab-deficient mice can primarily be attributed to the loss of STAT5b.

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Modulation of fatty acid elongation in cockroaches sustains sexually dimorphic hydrocarbons and female attractiveness

PLoS Biology ◽

10.1371/journal.pbio.3001330 ◽

2021 ◽

Vol 19 (7) ◽

pp. e3001330

Author(s):

Xiao-Jin Pei ◽

Yong-Liang Fan ◽

Yu Bai ◽

Tian-Tian Bai ◽

Coby Schal ◽

...

Keyword(s):

Fatty Acid ◽

Sex Pheromone ◽

Molecular Mechanism ◽

Sex Differentiation ◽

Biological Significance ◽

Sexually Dimorphic ◽

Contact Sex Pheromone ◽

Fatty Acid Elongase ◽

Female Specific ◽

Male Specific

Insect cuticular hydrocarbons (CHCs) serve as important intersexual signaling chemicals and generally show variation between the sexes, but little is known about the generation of sexually dimorphic hydrocarbons (SDHCs) in insects. In this study, we report the molecular mechanism and biological significance that underlie the generation of SDHC in the German cockroach Blattella germanica. Sexually mature females possess more C29 CHCs, especially the contact sex pheromone precursor 3,11-DimeC29. RNA interference (RNAi) screen against the fatty acid elongase family members combined with heterologous expression of the genes in yeast revealed that both BgElo12 and BgElo24 were involved in hydrocarbon (HC) production, but BgElo24 is of wide catalytic activities and is able to provide substrates for BgElo12, and only the female-enriched BgElo12 is responsible for sustaining female-specific HC profile. Repressing BgElo12 masculinized the female CHC profile, decreased contact sex pheromone level, and consequently reduced the sexual attractiveness of female cockroaches. Moreover, the asymmetric expression of BgElo12 between the sexes is modulated by sex differentiation cascade. Specifically, male-specific BgDsx represses the transcription of BgElo12 in males, while BgTra is able to remove this effect in females. Our study reveals a novel molecular mechanism responsible for the formation of SDHCs and also provide evidences on shaping of the SDHCs by sexual selection, as females use them to generate high levels of contact sex pheromone.

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STUDIES ON THE SEX-SPECIFIC LETHALS OF DROSOPHILA MELANOGASTER. V. SEX TRANSFORMATION CAUSED BY INTERACTIONS BETWEEN A FEMALE-SPECIFIC LETHAL, Sxl f#1, AND THE MALE-SPECIFIC LETHALS mle(3)132, msl-2 27, AND mle

Genetics ◽

10.1093/genetics/102.2.233 ◽

1982 ◽

Vol 102 (2) ◽

pp. 233-243

Author(s):

T Uenoyama ◽

A Fukunaga ◽

K Ioshi

Keyword(s):

Drosophila Melanogaster ◽

Morphological Changes ◽

External Genitalia ◽

Sexually Dimorphic ◽

Female Progeny ◽

Lethal Mutant ◽

Male Type ◽

Male Specific Lethal ◽

Female Specific ◽

Male Specific

ABSTRACT Interactions between a female-specific lethal mutant, Sxlf #1, and each of three male-specific lethal mutants, mle(3)132, msl-2 27 and mle, of Drosophila melanogaster were observed to produce morphological changes in various sexually dimorphic external characters. Chromosomal females heterozygous for Sxlf #1 and homozygous for any one of the male-specific lethals (and to a lesser degree heterozygous for male-specific lethals) sometimes had sex combs, male-type tergites, male-type sternites, male-type anal plates or male-type external genitalia. Penetrance was not high and expression was often incomplete; single individuals never had all the sexually dimorphic structures transformed. When mothers were homozygous for male-specific lethals, higher proportions of female progeny were affected than when mothers were heterozygous, suggesting a maternal effect.

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Sex-determining genes distinctly regulate courtship capability and target preference via sexually dimorphic neurons

eLife ◽

10.7554/elife.52701 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 5

Author(s):

Kenichi Ishii ◽

Margot Wohl ◽

Andre DeSouza ◽

Kenta Asahina

Keyword(s):

Aggressive Behavior ◽

Courtship Behavior ◽

Sexually Dimorphic ◽

Genetic Pathways ◽

Neuronal Populations ◽

Specific Enhancement ◽

Male Animal ◽

Courtship Behaviors ◽

Female Specific ◽

Male Specific

For successful mating, a male animal must execute effective courtship behaviors toward a receptive target sex, which is female. Whether the courtship execution capability and upregulation of courtship toward females are specified through separable sex-determining genetic pathways remains uncharacterized. Here, we found that one of the two Drosophila sex-determining genes, doublesex (dsx), specifies a male-specific neuronal component that serves as an execution mechanism for courtship behavior, whereas fruitless (fru) is required for enhancement of courtship behavior toward females. The dsx-dependent courtship execution mechanism includes a specific subclass within a neuronal cluster that co-express dsx and fru. This cluster contains at least another subclass that is specified cooperatively by both dsx and fru. Although these neuronal populations can also promote aggressive behavior toward male flies, this capacity requires fru-dependent mechanisms. Our results uncover how sex-determining genes specify execution capability and female-specific enhancement of courtship behavior through separable yet cooperative neurogenetic mechanisms.

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Postnatally Elevated Levels of Insulin-Like Growth Factor (IGF)-II Fail to Rescue the Dwarfism of IGF-I-Deficient Mice except Kidney Weight

Endocrinology ◽

10.1210/en.2006-0385 ◽

2007 ◽

Vol 148 (1) ◽

pp. 441-451 ◽

Cited By ~ 26

Author(s):

Corinna Moerth ◽

Marlon R. Schneider ◽

Ingrid Renner-Mueller ◽

Andreas Blutke ◽

Martin W. Elmlinger ◽

...

Keyword(s):

Phosphoenolpyruvate Carboxykinase ◽

Binding Proteins ◽

Genetic Model ◽

Body Weight Gain ◽

Postnatal Period ◽

Male Mice ◽

Intact Male ◽

Kidney Weight ◽

Igf I ◽

Deficient Mice

This study tested whether elevated levels of IGF-II in the postnatal period can rescue the dwarfism in IGF-I-deficient mice. Heterozygous Igf1 mutant mice [I+/− IIwt] were crossed with heterozygous Igf1 mutant, phosphoenolpyruvate carboxykinase promoter IGF-II transgenic mice [I+/− IItg], and [I+/+ IIwt], [I+/+ IItg], [I−/− IIwt], and [I−/− IItg] offspring were investigated. IGF-II levels were 11- and 6-fold higher in male and female [I−/− IItg] vs. [I−/− IIwt] animals. Western ligand blot analysis revealed markedly reduced activities of 30- and 32-kDa IGF binding proteins (IGFBPs) (most likely IGFBP-1 and IGFBP-2) and the 39- to 43-kDa IGFBP-3 double band in serum from IGF-I-deficient mice. These binding proteins were partially restored by overexpression of IGF-II. Analysis of weight data from the early postnatal period until d 60 showed that, in the absence of IGF-I, elevated levels of IGF-II have no effect on body weight gain. A detailed analysis of body proportions, bone parameters, and organ weights of 60-d-old mice also failed to show effects of IGF-II with one important exception: in Igf1 mutant and also Igf1 intact male mice, IGF-II overexpression significantly increased absolute (+32.4 and +28.6%; P < 0.01) and relative kidney weights (+29.0 and +22.4%; P < 0.001). These changes in kidney weight were associated with reduced phosphorylation of p38 MAPK. In summary, our genetic model shows that substantial amounts of IGF-II in the circulation do not rescue the postnatal growth deficit of IGF-I-deficient mice but increase absolute and relative kidney weights of normal and IGF-I-deficient male mice, suggesting a gender-specific role of IGF-II for kidney growth.

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Radiation-induced toxicity in rectal epithelial stem cell contributes to acute radiation injury in rectum

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02111-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Felipe Rodriguez Tirado ◽

Payel Bhanja ◽

Eduardo Castro-Nallar ◽

Ximena Diaz Olea ◽

Catalina Salamanca ◽

...

Keyword(s):

Stem Cells ◽

Ex Vivo ◽

Cre Recombinase ◽

Lineage Tracing ◽

Common Side Effect ◽

Rectal Injury ◽

Male Mice ◽

Pelvic Irradiation ◽

Pelvic Malignancies ◽

Radiation Induced

Abstract Background Radiation-induced rectal epithelial damage is a very common side effect of pelvic radiotherapy and often compromise the life quality and treatment outcome in patients with pelvic malignancies. Unlike small bowel and colon, effect of radiation in rectal stem cells has not been explored extensively. Here we demonstrate that Lgr5-positive rectal stem cells are radiosensitive and organoid-based transplantation of rectal stem cells mitigates radiation damage in rectum. Methods C57Bl6 male mice (JAX) at 24 h were exposed to pelvic irradiation (PIR) to determine the radiation effect in pelvic epithelium. Effect of PIR on Lgr5-positive rectal stem cells (RSCs) was determined in Lgr5-EGFP-Cre-ERT2 mice exposed to PIR. Effect of PIR or clinically relevant fractionated PIR on regenerative response of Lgr5-positive RSCs was examined by lineage tracing assay using Lgr5-eGFP-IRES-CreERT2; Rosa26-CAG-tdTomato mice with tamoxifen administration to activate Cre recombinase and thereby marking the ISC and their respective progeny. Ex vivo three-dimensional organoid cultures were developed from Lgr5-EGFP-Cre-ERT2 mice. Organoid growth was determined by quantifying the budding crypt/total crypt ratio. Organoids from Lgr5-EGFP-ires-CreERT2-TdT mice were transplanted in C57Bl6 male mice exposed to PIR. Engraftment and repopulation of Lgr5-positive RSCs were determined after tamoxifen administration to activate Cre recombinase in recipient mice. Statistical analysis was performed using Log-rank (Mantel-Cox) test and paired two-tail t test. Result Exposure to pelvic irradiation significantly damaged rectal epithelium with the loss of Lgr5+ve rectal stem cells. Radiosensitivity of rectal epithelium was also observed with exposure to clinically relevant fractionated pelvic irradiation. Regenerative capacity of Lgr5+ve rectal stem cells was compromised in response to fractionated pelvic irradiation. Ex vivo organoid study demonstrated that Lgr5+ve rectal stem cells are sensitive to both single and fractionated radiation. Organoid-based transplantation of Lgr5+ve rectal stem cells promotes repair and regeneration of rectal epithelium. Conclusion Lgr5-positive rectal stem cells are radiosensitive and contribute to radiation-induced rectal epithelial toxicity. Transplantation of Lgr5-positive rectal stem cells mitigates radiation-induced rectal injury and promotes repair and regeneration process in rectum.

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Pleiotropic Roles of the Orthologue of the Drosophila melanogaster Intersex Gene in the Brown Planthopper

Genes ◽

10.3390/genes12030379 ◽

2021 ◽

Vol 12 (3) ◽

pp. 379

Author(s):

Hou-Hong Zhang ◽

Yu-Cheng Xie ◽

Han-Jing Li ◽

Ji-Chong Zhuo ◽

Chuan-Xi Zhang

Keyword(s):

Drosophila Melanogaster ◽

Reproductive System ◽

Splice Variants ◽

Brown Planthopper ◽

Nilaparvata Lugens ◽

Vital Role ◽

Sexually Dimorphic ◽

Specific Product ◽

Reproductive Ability ◽

Female Specific

Intersex(ix), a gene involved in the sex-determining cascade of Drosophila melanogaster, works in concert with the female-specific product of doublesex (dsx) at the end of the hierarchy to implement the sex-specific differentiation of sexually dimorphic characters in female individuals. In this study, the ix homolog was identified in the brown planthopper (BPH), Nilaparvata lugens, which contained two splice variants expressed in both female and male insects. We found that Nlix played a vital role in the early nymphal development of BPH, showing an accumulated effect. RNAi-mediated knockdown of Nlix at 4th instar led to the external genital defects in both sexes, consequently resulting in the loss of reproductive ability in female and male individuals. After dsRNA injection, the males were normal on testes, while the females had defective ovarian development. Nlix was also required for early embryogenesis. Notably, when the dsNlix microinjection was performed in newly emerged females, the copulatory bursas were abnormally enlarged while the other tissues of the reproductive system developed normally. Our results demonstrated the pleiotropic roles of Nlix in embryogenesis and development of the reproductive system in a hemimetabolous insect species.

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Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice

Translational Psychiatry ◽

10.1038/s41398-021-01233-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Freddy Zhang ◽

Benjamin Rein ◽

Ping Zhong ◽

Treefa Shwani ◽

Megan Conrow-Graham ◽

...

Keyword(s):

Pyramidal Neurons ◽

Social Preference ◽

Intervention Strategy ◽

Autism Spectrum ◽

Synaptic Function ◽

Pharmacological Intervention ◽

Therapeutic Effects ◽

Male Mice ◽

Behavioral Abnormalities ◽

Deficient Mice

AbstractAutism spectrum disorder (ASD) is a lifelong developmental disorder characterized by social deficits and other behavioral abnormalities. Dysregulation of epigenetic processes, such as histone modifications and chromatin remodeling, have been implicated in ASD pathology, and provides a promising therapeutic target for ASD. Haploinsufficiency of the SHANK3 gene is causally linked to ASD, so adult (3–5 months old) Shank3-deficient male mice were used in this drug discovery study. We found that combined administration of the class I histone deacetylase inhibitor Romidepsin and the histone demethylase LSD1 inhibitor GSK-LSD1 persistently ameliorated the autism-like social preference deficits, while each individual drug alone was largely ineffective. Another behavioral abnormality in adult Shank3-deficient male mice, heightened aggression, was also alleviated by administration of the dual drugs. Furthermore, Romidepsin/GSK-LSD1 treatment significantly increased transcriptional levels of NMDA receptor subunits in prefrontal cortex (PFC) of adult Shank3-deficient mice, resulting in elevated synaptic expression of NMDA receptors and the restoration of NMDAR synaptic function in PFC pyramidal neurons. These results have offered a novel pharmacological intervention strategy for ASD beyond early developmental periods.

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Effects of Muclin (Dmbt1) deficiency on the gastrointestinal system

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00525.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. G717-G727 ◽

Cited By ~ 21

Author(s):

Robert C. De Lisle ◽

Weihong Xu ◽

Bruce A. Roe ◽

Donna Ziemer

Keyword(s):

Tumor Suppressor ◽

Disease Severity ◽

Exocrine Pancreas ◽

Body Weight Gain ◽

Exocrine Pancreatic Function ◽

Immune Defense ◽

Amylase Release ◽

Releasable Pool ◽

Significant Difference ◽

Deficient Mice

The Dmbt1 gene encodes alternatively spliced glycoproteins that are either membrane-associated or secreted epithelial products. Functions proposed for Dmbt1 include it being a tumor suppressor, having roles in innate immune defense and inflammation, and being a Golgi-sorting receptor in the exocrine pancreas. The heavily sulfated membrane glycoprotein mucin-like glycoprotein (Muclin) is a Dmbt1 product that is strongly expressed in organs of the gastrointestinal (GI) system. To explore Muclin's functions in the GI system, the Dmbt1 gene was targeted to produce Muclin-deficient mice. Muclin-deficient mice have normal body weight gain and are fertile. The Muclin-deficient mice did not develop GI tumors, even when crossed with mice lacking the known tumor suppressor p53. When colitis was induced by dextran sulfate sodium, there was no significant difference in disease severity in Muclin-deficient mice. Also, when acute pancreatitis was induced with supraphysiological caerulein, there was no difference in disease severity in the Muclin-deficient mice. Exocrine pancreatic function was impaired, as measured by attenuated neurohormonal-stimulated amylase release from Muclin-deficient acinar cells. Also, by [35S]Met/Cys pulse-chase analysis, traffic of newly synthesized protein to the stimulus-releasable pool was significantly retarded in Muclin-deficient cells compared with wild type. Thus Muclin deficiency impairs trafficking of regulated proteins to a stimulus-releasable pool in the exocrine pancreas.

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Abstract P199: Mas Receptor Deficiency Regulates Obesity-Hypertension and Cardiac Function in Female and Male Mice

Hypertension ◽

10.1161/hyp.68.suppl_1.p199 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Robin C Shoemaker ◽

Yu Wang ◽

Sean Thatcher ◽

Lisa Cassis

Keyword(s):

Blood Pressure ◽

Sexual Dimorphism ◽

Cardiac Function ◽

Male Mice ◽

Reduced Ejection Fraction ◽

Obesity Hypertension ◽

Obese Male ◽

Deficient Mice ◽

Cmr Imaging

Angiotensin-1-7 (Ang-(1-7)) counteracts angiotensin II through effects at Mas receptors (MasR). We demonstrated that sexual dimorphism of obesity-hypertension was associated with dysregulated production of Ang-(1-7). However, the role of MasR in sexual dimorphism of obesity-hypertension has not been examined. MasR deficient mice have also been reported to exhibit deficits in cardiac function. In this study, we hypothesized that deficiency of the MasR would differentially regulate obesity-hypertension in male versus ( vs ) female mice. In addition, we quantified effects of MasR deficiency on cardiac function in obese male mice. Male and female MasR +/+ and -/- mice were fed a low fat (LF, 10%kcal) or high fat (HF, 60% kcal) diet for 16 weeks, and blood pressure was quantified by radiotelemetry. As demonstrated previously, male MasR +/+ mice (24 hr diastolic blood pressure, DBP: LF, 90 ± 3; HF, 96 ± 2 mmHg; P<0.05), but not females (LF, 85 ± 1; HF, 85 ± 2 mmHg), developed hypertension in response to HF feeding. MasR deficiency converted female HF-fed mice to an obesity-hypertension phenotype (DBP: 92 ± 1 mmHg; P<0.05). Surprisingly, male HF-fed MasR -/- mice exhibited reduced DBP compared to HF-fed MasR +/+ males (90 ± 1 vs 96 ± 2 mmHg; P<0.05). To define mechanisms for reductions in DBP of HF-fed male MasR -/- mice, we performed cardiac magnetic resonance (CMR) imaging in both genotypes at 1 month of HF feeding. MasR -/- mice had significantly reduced ejection fraction (EF) compared to MasR +/+ mice at baseline (51.4 ± 2.5 vs 59.3 ± 2.1%; P<0.05) and after one month of HF-feeding (49.8 ± 2.4 vs 52.6 ± 1.9%; P<0.05). Further, CMR imaging demonstrated a thickening of the ventricle wall in MasR -/- mice with 1 month of HF-feeding. MasR +/+ , but not MasR -/- mice, exhibited diet-induced reductions in EF (by 16%; P<0.05) at 1 month of HF feeding, which were reversed by infusion of Ang-(1-7). These results demonstrate that MasR contributes to sexual dimorphism of obesity-hypertension. Ang-(1-7) protects females from obesity-hypertension through the MasR. In contrast, reductions in DBP in obese male mice with MasR deficiency may arise from deficits in cardiac function. These results suggest that MasR agonists may be effective therapies for obesity-associated cardiovascular conditions.

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