title: GDNF-mediated signaling via RET tyrosine 1062 is essential for maintenance of spermatogonial stem cells.
abstract: Well-organized spermatogenesis, including the maintenance of spermatogonial stem cells (SSCs), is indispensable for continuous male fertility. Signaling by glial cell line-derived neurotrophic factor (GDNF) via the RET/GDNF family receptor alpha1 (GFRalpha1) receptor complex is essential for self-renewal of murine SSCs and may also regulate their differentiation. When phosphorylated, tyrosine 1062 in RET presents a binding site for the phosphotyrosine-binding domains of several adaptor and effector proteins that are important for activation of a variety of intracellular signaling pathways. In this study, we investigated the role of signaling via RET tyrosine 1062 in spermatogenesis using RET Y1062F knockin mice (Y1062F mice), in which tyrosine 1062 was replaced with phenylalanine. Homozygous Y1062F mice showed marked atrophy of testes due to reduced production of germ cells. RET-expressing spermatogonia in seminiferous tubules of homozygous Y1062F mice decreased after postnatal day (P) 7 and germ cells were almost undetectable by P21. These phenomena appeared to be due to a lack of SSC self-renewal and inability to maintain the undifferentiated state. Our findings suggest that RET signaling via tyrosine 1062 is essential for self-renewal of SSCs and regulation of their differentiation.
authors: Department of Pathology, Nagoya University Graduate School of Medicine 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors: Mayumi
authors: M
authors: Jijiwa
authors: Kumi
authors: K
authors: Kawai
authors: Jun
authors: J
authors: Fukihara
authors: Akari
authors: A
authors: Nakamura
authors: Masaki
authors: M
authors: Hasegawa
authors: Chikage
authors: C
authors: Suzuki
authors: Tomoko
authors: T
authors: Sato
authors: Atsushi
authors: A
authors: Enomoto
authors: Naoya
authors: N
authors: Asai
authors: Yoshiki
authors: Y
authors: Murakumo
authors: Masahide
authors: M
authors: Takahashi
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000502:physiology*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation; D051096:Proto-Oncogene Proteins c-ret / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013091:Spermatogenesis / Q000502:physiology; D013093:Spermatogonia / Q000166:cytology* / Q000378:metabolism; D013737:Testis / Q000166:cytology; D014443:Tyrosine / Q000737:chemistry
chemical_list: C495040:Gdnf protein, mouse; C494988:Gfra1 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D011994:Recombinant Proteins; D014443:Tyrosine; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse