Haploinsufficiency of Dmxl2, Encoding a Synaptic Protein, Causes Infertility Associated with a Loss of GnRH Neurons in Mouse

PLoS Biology

Volumn 12, Issue 9, 2014, Pages

  Tata, Brooke ^a,b   Huijbregts, Lukas ^a,b   Jacquier, Sandrine ^a   Csaba, Zsolt ^a   Genin, Emmanuelle ^a   Meyer, Vincent ^c   Leka, Sofia ^a   Dupont, Joelle ^d   Charles, Perrine ^a   Chevenne, Didier ^e   Carel, Jean Claude ^a,b,e   Léger, Juliane ^a,b,e   de Roux, Nicolas ^a,b,e  

^a INSERM   (France)

^b UNIVERSITÉ PARIS DESCARTES   (France)

^c CENTRE NATIONAL DE SÉQUENÇAGE   (France)

^d UMR85 PHYSIOLOGIE DE LA REPRODUCTION ET DES COMPORTEMENTS   (France)

^e HÔPITAL ROBERT DEBRÉ   (France)

Author keywords

[No Author keywords available]

Indexed keywords

C PEPTIDE; FOLLITROPIN; GONADORELIN; HEMOGLOBIN A1C; INSULIN; LUTEINIZING HORMONE; RABCONNECTIN 3ALPHA; SCAFFOLD PROTEIN; TESTOSTERONE; UNCLASSIFIED DRUG; DMXL2 PROTEIN, HUMAN; NERVE PROTEIN; SIGNAL TRANSDUCING ADAPTOR PROTEIN;

ADOLESCENT; ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BLOOD LEVEL; BRAIN NERVE CELL; CASE REPORT; CELL LOSS; CONTROLLED STUDY; DELAYED PUBERTY; DISEASE COURSE; DMXL2 GENE; FEMALE; GENE; GENE DELETION; GENE EXPRESSION; GENE FUNCTION; GENE LOCATION; GLUCOSE METABOLISM; HAPLOINSUFFICIENCY; HIGH THROUGHPUT SEQUENCING; HOMOZYGOTE; HUMAN; HYPOGONADISM; HYPOPHYSIS; HYPOTHALAMUS; HYPOTHALAMUS HYPOPHYSIS SYSTEM; INFERTILITY; INSULIN RELEASE; MALE; MOUSE; NONHUMAN; PHENOTYPE; PROTEIN FUNCTION; SEXUAL INFANTILISM; ANIMAL; DEFICIENCY; GENETICS; GROWTH, DEVELOPMENT AND AGING; HYPOGLYCEMIA; HYPOTHYROIDISM; INSULIN DEPENDENT DIABETES MELLITUS; INTELLECTUAL IMPAIRMENT; KNOCKOUT MOUSE; MALE INFERTILITY; METABOLISM; MOLECULAR GENETICS; NERVE CELL; NUCLEOTIDE SEQUENCE; PATHOLOGY; POLYNEUROPATHY; SEXUAL MATURATION; SYNDROME; TESTIS; YOUNG ADULT;

MUS;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ADOLESCENT; ANIMALS; BASE SEQUENCE; DIABETES MELLITUS, TYPE 1; FOLLICLE STIMULATING HORMONE; GONADOTROPIN-RELEASING HORMONE; HAPLOINSUFFICIENCY; HOMOZYGOTE; HUMANS; HYPOGLYCEMIA; HYPOTHALAMUS; HYPOTHYROIDISM; INFERTILITY, MALE; INTELLECTUAL DISABILITY; LUTEINIZING HORMONE; MALE; MICE; MICE, KNOCKOUT; MOLECULAR SEQUENCE DATA; NERVE TISSUE PROTEINS; NEURONS; PITUITARY GLAND; POLYNEUROPATHIES; SEQUENCE DELETION; SEXUAL MATURATION; SYNDROME; TESTIS; YOUNG ADULT;

EID: 84920405426     PISSN: 15449173     EISSN: 15457885     Source Type: Journal    
DOI: 10.1371/journal.pbio.1001952     Document Type: Article

References (57)

1. Sisk CL, Foster DL, (2004) The neural basis of puberty and adolescence. Nat Neurosci 7: 1040–1047.
2. Plant TM, Witchel SF (2006) Puberty in nonhuman primates and humans. In: Neill JD, editor. Knobil and Neil's physiology of reproduction. St Louis, MO: Elsevier. pp. 2177–2230.
3. Iremonger KJ, Constantin S, Liu X, Herbison AE, (2010) Glutamate regulation of GnRH neuron excitability. Brain Res 1364: 35–43.
4. Ojeda SR, Lomniczi A, Sandau U, Matagne V, (2010) New concepts on the control of the onset of puberty. Endocr Dev 17: 44–51.
5. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M, (2012) Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev 92: 1235–1316.
6. Goodman RL, Lehman MN, (2012) Kisspeptin neurons from mice to men: similarities and differences. Endocrinology 153: 5105–5118.
7. Lomniczi A, Loche A, Castellano JM, Ronnekleiv OK, Bosch M, et al. (2013) Epigenetic control of female puberty. Nat Neurosci 16: 281–289.
8. de Roux N, Young J, Misrahi M, Genet R, Chanson P, et al. (1997) A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med 337: 1597–1602.
9. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, et al. (2003) Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 100: 10972–10976.
10. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS, Jret al. (2003) The GPR54 gene as a regulator of puberty. N Engl J Med 349: 1614–1627.
11. Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, et al. (2012) Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 366: 629–635.
12. Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, et al. (2009) TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 41: 354–358.
13. Navarro VM, (2013) Interactions between kisspeptins and neurokinin B. Adv Exp Med Biol 784: 325–347.
14. Dode C, Hardelin JP, (2010) Clinical genetics of Kallmann syndrome. Ann Endocrinol (Paris) 71: 149–157.
15. Pitteloud N, Durrani S, Raivio T, Sykiotis GP, (2010) Complex genetics in idiopathic hypogonadotropic hypogonadism. Front Horm Res 39: 142–153.
16. Wray S, (2010) From nose to brain: development of gonadotrophin-releasing hormone-1 neurones. J Neuroendocrinol 22: 743–753.
17. Alazami AM, Al-Saif A, Al-Semari A, Bohlega S, Zlitni S, et al. (2008) Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet 83: 684–691.
18. Aligianis IA, Johnson CA, Gissen P, Chen D, Hampshire D, et al. (2005) Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nat Genet 37: 221–223.
19. Aligianis IA, Morgan NV, Mione M, Johnson CA, Rosser E, et al. (2006) Mutation in Rab3 GTPase-activating protein (RAB3GAP) noncatalytic subunit in a kindred with Martsolf syndrome. Am J Hum Genet 78: 702–707.
20. Bernard G, Chouery E, Putorti ML, Tetreault M, Takanohashi A, et al. (2011) Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet 89: 415–423.
21. Tetreault M, Choquet K, Orcesi S, Tonduti D, Balottin U, et al. (2011) Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy. Am J Hum Genet 89: 652–655.
22. Houseley J, Tollervey D, (2009) The many pathways of RNA degradation. Cell 136: 763–776.
23. Kawabe H, Sakisaka T, Yasumi M, Shingai T, Izumi G, et al. (2003) A novel rabconnectin-3-binding protein that directly binds a GDP/GTP exchange protein for Rab3A small G protein implicated in Ca(2+)-dependent exocytosis of neurotransmitter. Genes Cells 8: 537–546.
24. Nagano F, Kawabe H, Nakanishi H, Shinohara M, Deguchi-Tawarada M, et al. (2002) Rabconnectin-3, a novel protein that binds both GDP/GTP exchange protein and GTPase-activating protein for Rab3 small G protein family. J Biol Chem 277: 9629–9632.
25. Sethi N, Yan Y, Quek D, Schupbach T, Kang Y, (2010) Rabconnectin-3 is a functional regulator of mammalian Notch signaling. J Biol Chem 285: 34757–34764.
26. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, et al. (2011) A conditional knockout resource for the genome-wide study of mouse gene function. Nature 474: 337–342.
27. Skarnes WC, (2005) Two ways to trap a gene in mice. Proc Natl Acad Sci U S A 102: 13001–13002.
28. Guan C, Ye C, Yang X, Gao J, (2010) A review of current large-scale mouse knockout efforts. Genesis 48: 73–85.
29. Dubois NC, Hofmann D, Kaloulis K, Bishop JM, Trumpp A, (2006) Nestin-Cre transgenic mouse line Nes-Cre1 mediates highly efficient Cre/loxP mediated recombination in the nervous system, kidney, and somite-derived tissues. Genesis 44: 355–360.
30. Dehorter N, Michel FJ, Marissal T, Rotrou Y, Matrot B, et al. (2011) Onset of Pup locomotion coincides with loss of NR2C/D-mediated cortico-striatal EPSCs and dampening of striatal network immature activity. Front Cell Neurosci 5: 24.
31. Hutagalung AH, Novick PJ, (2011) Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev 91: 119–149.
32. Burgoyne RD, Morgan A, (2003) Secretory granule exocytosis. Physiol Rev 83: 581–632.
33. Jacobsson G, Bean AJ, Scheller RH, Juntti-Berggren L, Deeney JT, et al. (1994) Identification of synaptic proteins and their isoform mRNAs in compartments of pancreatic endocrine cells. Proc Natl Acad Sci U S A 91: 12487–12491.
34. Handley MT, Aligianis IA, (2012) RAB3GAP1, RAB3GAP2 and RAB18: disease genes in Micro and Martsolf syndromes. Biochem Soc Trans 40: 1394–1397.
35. Wierman ME, Kiseljak-Vassiliades K, Tobet S, (2011) Gonadotropin-releasing hormone (GnRH) neuron migration: initiation, maintenance and cessation as critical steps to ensure normal reproductive function. Front Neuroendocrinol 32: 43–52.
36. Tuttle AM, Hoffman TL, Schilling TF, (2014) Rabconnectin-3a regulates vesicle endocytosis and canonical Wnt signaling in zebrafish neural crest migration. PLoS Biol 12: e1001852.
37. Carel JC, Boitard C, Bougneres PF, (1993) Decreased insulin response to glucose in islet cell antibody-negative siblings of type 1 diabetic children. J Clin Invest 92: 509–513.
38. Huyghe JR, Jackson AU, Fogarty MP, Buchkovich ML, Stancakova A, et al. (2013) Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion. Nat Genet 45: 197–201.
39. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42: 105–116.
40. Izumi T, Gomi H, Kasai K, Mizutani S, Torii S, (2003) The roles of Rab27 and its effectors in the regulated secretory pathways. Cell Struct Funct 28: 465–474.
41. Geppert M, Goda Y, Stevens CF, Sudhof TC, (1997) The small GTP-binding protein Rab3A regulates a late step in synaptic vesicle fusion. Nature 387: 810–814.
42. Sakane A, Manabe S, Ishizaki H, Tanaka-Okamoto M, Kiyokage E, et al. (2006) Rab3 GTPase-activating protein regulates synaptic transmission and plasticity through the inactivation of Rab3. Proc Natl Acad Sci U S A 103: 10029–10034.
43. Geppert M, Bolshakov VY, Siegelbaum SA, Takei K, De Camilli P, et al. (1994) The role of Rab3A in neurotransmitter release. Nature 369: 493–497.
44. Figueiredo AC, Wasmeier C, Tarafder AK, Ramalho JS, Baron RA, et al. (2008) Rab3GEP is the non-redundant guanine nucleotide exchange factor for Rab27a in melanocytes. J Biol Chem 283: 23209–23216.
45. Yamaguchi K, Tanaka M, Mizoguchi A, Hirata Y, Ishizaki H, et al. (2002) A GDP/GTP exchange protein for the Rab3 small G protein family up-regulates a postdocking step of synaptic exocytosis in central synapses. Proc Natl Acad Sci U S A 99: 14536–14541.
46. Yan Y, Denef N, Schupbach T, (2009) The vacuolar proton pump, V-ATPase, is required for notch signaling and endosomal trafficking in Drosophila. Dev Cell 17: 387–402.
47. Einhorn Z, Trapani JG, Liu Q, Nicolson T, (2012) Rabconnectin3alpha promotes stable activity of the H+ pump on synaptic vesicles in hair cells. J Neurosci 32: 11144–11156.
48. Ruschendorf F, Nurnberg P, (2005) ALOHOMORA: a tool for linkage analysis using 10K SNP array data. Bioinformatics 21: 2123–2125.
49. Gudbjartsson DF, Thorvaldsson T, Kong A, Gunnarsson G, Ingolfsdottir A, (2005) Allegro version 2. Nat Genet 37: 1015–1016.
50. Khalfallah O, Faucon-Biguet N, Nardelli J, Meloni R, Mallet J, (2008) Expression of the transcription factor Zfp191 during embryonic development in the mouse. Gene Expr Patterns 8: 148–154.
51. Villanueva C, Jacquier S, de Roux N, (2012) DLK1 is a somato-dendritic protein expressed in hypothalamic arginine-vasopressin and oxytocin neurons. PLoS ONE 7: e36134.
52. Wray S, Gahwiler BH, Gainer H, (1988) Slice cultures of LHRH neurons in the presence and absence of brainstem and pituitary. Peptides 9: 1151–1175.
53. Chung WC, Matthews TA, Tata BK, Tsai PS, (2010) Compound deficiencies in multiple fibroblast growth factor signalling components differentially impact the murine gonadotrophin-releasing hormone system. J Neuroendocrinol 22: 944–950.
54. Dumoulin A, Rostaing P, Bedet C, Levi S, Isambert MF, et al. (1999) Presence of the vesicular inhibitory amino acid transporter in GABAergic and glycinergic synaptic terminal boutons. J Cell Sci 112 (Pt 6) 811–823.
55. Merglen A, Theander S, Rubi B, Chaffard G, Wollheim CB, et al. (2004) Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells. Endocrinology 145: 667–678.
56. Tosca L, Froment P, Rame C, McNeilly JR, McNeilly AS, et al. (2011) Metformin decreases GnRH- and activin-induced gonadotropin secretion in rat pituitary cells: potential involvement of adenosine 5′ monophosphate-activated protein kinase (PRKA). Biol Reprod 84: 351–362.
57. Seol JH, Shevchenko A, Shevchenko A, Deshaies RJ, (2001) Skp1 forms multiple protein complexes, including RAVE, a regulator of V-ATPase assembly. Nat Cell Biol 3: 384–391.