Ben Davies

Publications (6)16.76 Total impact

• Article: Adhesion-GPCRs in the male reproductive tract.

  Ben Davies, Christiane Kirchhoff
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  ABSTRACT: The male reproductive tract expresses a diverse array of adhesion-GPCRs, many in a highly specific and regulated manner. Despite this specificity of expression, little is known about the function of this receptor family in male reproductive physiology. Insights into function are beginning to emerge with the increasing availability of genetically modified mice harbouring mutations in these genes. Gpr64 is the best characterised of the adhesion-GPCRs in the male reproductive system and the phenotype of Gpr64 knock-out mice implicates this receptor in the regulation of fluid absorption in the efferent ducts and proximal epididymis. This chapter summarizes recent data concerning this receptor and other family members in the male reproductive system.
  Advances in experimental medicine and biology 01/2010; 706:179-88. · 1.09 Impact Factor
• Article: Novel epididymis-specific mRNAs downregulated by HE6/Gpr64 receptor gene disruption.

  Ben Davies, Martina Behnen, Heike Cappallo-Obermann, Andrej-Nikolai Spiess, Franz Theuring, Christiane Kirchhoff
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  ABSTRACT: Targeted disruption of the epididymis-specific HE6/Gpr64 receptor gene in mice led to male infertility. In order to characterize the phenotype at a molecular level, we compared the gene expression patterns of wild type (wt) versus knockout (KO) caput epididymides. The caput region of KO males, although morphologically normal, nevertheless showed an aberrant expression pattern. Combining micro array analysis, differential library screening, Northern blot analysis and quantitative RT-PCR, we found that the knockout of the HE6/Gpr64 receptor was mainly associated with the downregulation of genes specific to the initial segment. The list of KO downregulated transcripts comprised Enpp2/autotaxin, the lipocalins 8 and 9, the beta-defensin Defb42, cystatins 8 and 12, as well as the membrane proteins Adam (A Disintegrin And Metalloprotease) 28, claudin-10, EAAC1, and the novel Me9. Clusterin/ApoJ and osteopontin/Spp1 mRNAs, on the other hand, were upregulated in the KO tissues. The Me9 transcript was studied in further detail, and we report here a cluster of related epididymis-specific genes. Me9 is specifically expressed in the initial segment and is representative of a novel and highly conserved mammalian gene family. The family consists of single-exon genes only; intron-containing paralogs have not yet been ascertained. The cloned cDNA sequences predicted hydrophobic polytopic membrane proteins containing the DUF716 motif. Protein expression was shown in the rodent caput epididymidis but remained uncertain in primates.
  Molecular Reproduction and Development 06/2007; 74(5):539-53. · 2.53 Impact Factor
• Article: New approaches for male fertility control: HE6 as an example of a putative target.

  Ulrich Gottwald, Ben Davies, Martin Fritsch, Ursula F Habenicht
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  ABSTRACT: Reversible contraceptive methods for males are still not available. During the last few years several marketing studies have clearly shown that men and women would welcome a situation where men could assume responsibility for family planning. Schering AG and Organon are currently collaborating to develop a hormonal method for male fertility control based on the combination of etonogestrel as gestagenic component and testosterone undecanoate. To further optimize male contraceptives in terms of improved efficiency, rapid onset, reversibility, fewer side effects and a convenient method of application, a search for innovative non-hormonal approaches was started. During the last few years, numerous proteins were identified which play a specific role in male fertility. These proteins have first to fulfil a set of indication-specific criteria before a drug discovery process can be initiated. The most important criteria for a putative target protein are tissue-selective expression, crucial biological function in fertility, drugable properties and feasibility of assay development for high-throughput-screening and lead optimization. The G-protein-coupled receptor HE6 was selected as target and the above selection criteria were applied. HE6 displays a preferred epididymis-specific expression pattern and belongs to the superfamily of GPCRs, which are well known to be drugable with small molecules. A knockout mouse was generated which revealed an infertility phenotype with the onset occurring 6 weeks after initiation of spermatogenesis at the latest. Surprisingly, no epididymis-specific phenotype was observed. Instead, the reabsorption of testicular fluid along the efferent ducts was strongly affected. No further obvious side effects were observed in male or female mice. This study with HE6 exemplifies how targets for male contraception have to be validated before drug development can start.
  Molecular and Cellular Endocrinology 06/2006; 250(1-2):49-57. · 4.19 Impact Factor
• Article: Mice over-expressing the 5-HT(1A) receptor in cortex and dentate gyrus display exaggerated locomotor and hypothermic response to 8-OH-DPAT.

  Bettina Bert, Heidrun Fink, Heide Hörtnagl, Rüdiger W Veh, Ben Davies, Franz Theuring, Heike Kusserow
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  ABSTRACT: The serotonin 1A (5-HT(1A)) receptor is one of the best described receptor subtypes of the serotonergic system. Due to the complex distribution pattern, the pre- and postsynaptic localisation, the impact on various monoamines, as well as the influence on a wide range of physiological functions, the contribution of 5-HT(1A) receptors to behavioural outcomes is difficult to define. In this study, we present a new transgenic mouse model with a prominent over-expression of the 5-HT(1A) receptor in the outer cortical layers (I-III) and the dentate gyrus. Behavioural studies revealed a slight decrease in baseline motor activity of homozygous mice during the open field test. Moreover, core body temperature of male transgenic mice was significantly lower than that of wild-type mice. Pharmacological studies with the 5-HT(1A) receptor agonist 8-OH-DPAT (0.1-2.5 mg/kg, i.p.) revealed an exaggerated drug response in mutant mice. 8-OH-DPAT led to a drastic decrease in motor activity in the open field and elevated plus maze test. This significant effect on motor activity became more apparent by investigating the serotonergic syndrome induced by 8-OH-DPAT. Concentration as low as 0.5 mg/kg 8-OH-DPAT caused immobility in transgenic mice for 30 min, head weaving behaviour, and backward walking, whereas in wild-type animals, typical behaviours of the serotonin syndrome were first observed at concentrations of 1.5 mg/kg and more. In addition, the 8-OH-DPAT induced hypothermia was more pronounced in mutant mice than in wild-type animals. Therefore, these genetically modified mice represent a promising model for further investigations of the role of 5-HT(1A) receptors.
  Behavioural Brain Research 03/2006; 167(2):328-41. · 3.42 Impact Factor
• Source

  Available from: ncbi.nlm.nih.gov

  Article: Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility.

  Ben Davies, Claudia Baumann, Christiane Kirchhoff, Richard Ivell, Reinhard Nubbemeyer, Ursula-Friederike Habenicht, Franz Theuring, Ulrich Gottwald
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  ABSTRACT: Human epididymal protein 6 (HE6; also known as GPR64) is an orphan member of the LNB-7TM (B(2)) subfamily of G-protein-coupled receptors. Family members are characterized by the dual presence of a secretin-like (type II) seven-transmembrane (7TM) domain and a long cell adhesion-like extracellular domain. HE6 is specifically expressed within the efferent ductules and the initial segment of the epididymis, ductal systems involved in spermatozoon maturation. Here, we report that targeted deletion of the 7TM domain of the murine HE6 gene results in male infertility. Mutant mice reveal a dysregulation of fluid reabsorbtion within the efferent ductules, leading to a backup of fluid accumulation in the testis and a subsequent stasis of spermatozoa within the efferent ducts. The fertility phenotype of HE6 knockout mice identifies this receptor as a potential nonsteroidal, nontesticular target for future male contraceptives and identifies an in vivo function for a member of this unusual gene family.
  Molecular and Cellular Biology 11/2004; 24(19):8642-8. · 5.53 Impact Factor
• Article: Mice over-expressing the 5-HT1A receptor in cortex and dentate gyrus display exaggerated locomotor and hypothermic response to 8-OH-DPAT

  Bettina Bert, Heidrun Fink, Heide Hörtnagl, Rüdiger W. Veh, Ben Davies, Franz Theuring, Heike Kusserow
  [show abstract] [hide abstract]
  ABSTRACT: The serotonin 1A (5-HT1A) receptor is one of the best described receptor subtypes of the serotonergic system. Due to the complex distribution pattern, the pre- and postsynaptic localisation, the impact on various monoamines, as well as the influence on a wide range of physiological functions, the contribution of 5-HT1A receptors to behavioural outcomes is difficult to define.In this study, we present a new transgenic mouse model with a prominent over-expression of the 5-HT1A receptor in the outer cortical layers (I–III) and the dentate gyrus. Behavioural studies revealed a slight decrease in baseline motor activity of homozygous mice during the open field test. Moreover, core body temperature of male transgenic mice was significantly lower than that of wild-type mice. Pharmacological studies with the 5-HT1A receptor agonist 8-OH-DPAT (0.1–2.5 mg/kg, i.p.) revealed an exaggerated drug response in mutant mice. 8-OH-DPAT led to a drastic decrease in motor activity in the open field and elevated plus maze test. This significant effect on motor activity became more apparent by investigating the serotonergic syndrome induced by 8-OH-DPAT. Concentration as low as 0.5 mg/kg 8-OH-DPAT caused immobility in transgenic mice for 30 min, head weaving behaviour, and backward walking, whereas in wild-type animals, typical behaviours of the serotonin syndrome were first observed at concentrations of 1.5 mg/kg and more. In addition, the 8-OH-DPAT induced hypothermia was more pronounced in mutant mice than in wild-type animals. Therefore, these genetically modified mice represent a promising model for further investigations of the role of 5-HT1A receptors.
  Behavioural Brain Research.