Mutant phenotype analysis suggests potential roles for C-type natriuretic peptide receptor (NPR-B) in male mouse fertility

Reproductive Biology and Endocrinology

Tsuneo Saga²  Tetsuo Kunieda³  Takako Furukawa²  Yukie Yoshii²  Yuka Ishida¹  Satoshi Tsukamoto¹  Yasuhiro Fujiwara³  Chizuru Sogawa⁴ 

[1] Laboratory Animal and Genome Sciences Section, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan;Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan;Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi, Okayama 700-8530, Japan;The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA

关键词: Spermatogenesis;    Infertility;    Paraphimosis;    Smooth muscle;    SLW mouse;    cGMP;    NPR-B;    CNP;   

Others  :  1139791
DOI  :  10.1186/1477-7827-12-64

 received in 2014-05-11, accepted in 2014-07-07,  发布年份 2014

【 摘 要 】

Background

C-type natriuretic peptide (CNP) signaling through its receptor natriuretic peptide receptor B (NPR-B) is a key molecule for mammalian reproduction, and known to play important roles in female fertility. However, the function of these peptides in mouse male reproduction remains largely unknown. To determine the role of CNP/NPR-B signaling in male reproduction we investigated phenotype of Npr2-deficient short-limbed-dwarfism (Npr2^slw/slw) mice, which have been shown to have gastrointestinal (GI) abnormalities.

Findings

In homozygous Npr2^slw/slw mice, spermatogenesis is developmentally delayed at both 2 and 4 weeks of age, with vacuolation and degenerating apoptotic germ cells being observed at 3 weeks age. However, the adult Npr2^slw/slw mice exhibited apparently normal spermatogenesis, albeit with some aberrant spermatids, suggesting that developmental delay was overcome. In addition, the adult Npr2^slw/slw mice showed abnormal penile morphology (paraphimosis).

Conclusions

The potential role of CNP signaling via the NPR-B receptor in male fertility appears to be mediated not through germ-cell development, but may be through maintenance of normal penile function.

【 授权许可】

   
2014 Sogawa et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 2.

【 参考文献 】

• [1]Potter LR, Hunter T: Guanylyl cyclase-linked natriuretic peptide receptors: structure and regulation. J Biol Chem 2001, 276:6057-6060.
• [2]Pyne NJ, Arshavsky V, Lochhead A: cGMP signal termination. Biochem Soc Trans 1996, 24:1019-1022.
• [3]Komatsu Y, Itoh H, Suga S, Ogawa Y, Hama N, Kishimoto I, Nakagawa O, Igaki T, Doi K, Yoshimasa T, Nakao K: Regulation of endothelial production of C-type natriuretic peptide in coculture with vascular smooth muscle cells. Role of the vascular natriuretic peptide system in vascular growth inhibition. Circ Res 1996, 78:606-614.
• [4]Minamino N, Aburaya M, Kojima M, Miyamoto K, Kangawa K, Matsuo H: Distribution of C-type natriuretic peptide and its messenger RNA in rat central nervous system and peripheral tissue. Biochem Biophys Res Commun 1993, 197:326-335.
• [5]Suga S, Nakao K, Itoh H, Komatsu Y, Ogawa Y, Hama N, Imura H: Endothelial production of C-type natriuretic peptide and its marked augmentation by transforming growth factor-beta. Possible existence of "vascular natriuretic peptide system". J Clin Invest 1992, 90:1145-1149.
• [6]Sogawa C, Wakizaka H, Aung W, Jin ZH, Tsuji AB, Furukawa T, Kunieda T, Saga T: C-type natriuretic peptide specifically acts on the pylorus and large intestine in mouse gastrointestinal tract. Am J Pathol 2013, 182:172-179.
• [7]Zhang M, Su YQ, Sugiura K, Xia G, Eppig JJ: Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes. Science 2010, 330:366-369.
• [8]Sogawa C, Tsuji T, Shinkai Y, Katayama K, Kunieda T: Short-limbed dwarfism: slw is a new allele of Npr2 causing chondrodysplasia. J Hered 2007, 98:575-580.
• [9]Geister KA, Brinkmeier ML, Hsieh M, Faust SM, Karolyi IJ, Perosky JE, Kozloff KM, Conti M, Camper SA: A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type. Hum Mol Genet 2013, 22:345-357.
• [10]Tamura N, Doolittle LK, Hammer RE, Shelton JM, Richardson JA, Garbers DL: Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs. Proc Natl Acad Sci U S A 2004, 101:17300-17305.
• [11]Middendorff R, Davidoff MS, Behrends S, Mewe M, Miethens A, Muller D: Multiple roles of the messenger molecule cGMP in testicular function. Andrologia 2000, 32:55-59.
• [12]Middendorff R, Muller D, Paust HJ, Holstein AF, Davidoff MS: New aspects of Leydig cell function. Adv Exp Med Biol 1997, 424:125-138.
• [13]Xia W, Mruk DD, Cheng CY: C-type natriuretic peptide regulates blood-testis barrier dynamics in adult rat testes. Proc Natl Acad Sci U S A 2007, 104:3841-3846.
• [14]Sogawa C, Abe A, Tsuji T, Koizumi M, Saga T, Kunieda T: Gastrointestinal tract disorder in natriuretic peptide receptor B gene mutant mice. Am J Pathol 2010, 177:822-828.
• [15]Horn MM, Ramos AR, Winkelmann L, Matte US, Goldani HA, Silveira TR: Seminiferous epithelium of rats with food restriction and carbon tetrachloride-induced cirrhosis. Int Braz J Urol 2006, 32:94-99. discussion 99
• [16]Wu A, Wan F, Sun X, Liu Y: Effects of dietary restriction on growth, neurobehavior, and reproduction in developing Kunmin mice. Toxicol Sci 2002, 70:238-244.
• [17]Kiyosu C, Tsuji T, Yamada K, Kajita S, Kunieda T: NPPC/NPR2 signaling is essential for oocyte meiotic arrest and cumulus oophorus formation during follicular development in the mouse ovary. Reproduction 2012, 144:187-193.
• [18]Santos AM, Ferraz MR, Teixeira CV, Sampaio FJ, da Fonte Ramos C: Effects of undernutrition on serum and testicular testosterone levels and sexual function in adult rats. Horm Metab Res 2004, 36:27-33.
• [19]Zambrano E, Rodriguez-Gonzalez GL, Guzman C, Garcia-Becerra R, Boeck L, Diaz L, Menjivar M, Larrea F, Nathanielsz PW: A maternal low protein diet during pregnancy and lactation in the rat impairs male reproductive development. J Physiol 2005, 563:275-284.
• [20]Glossmann H, Petrischor G, Bartsch G: Molecular mechanisms of the effects of sildenafil (VIAGRA). Exp Gerontol 1999, 34:305-318.