GDNF-mediated signaling via RET tyrosine 1062 is essential for maintenance of spermatogonial stem cells.
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.
Jijiwa
Mayumi
M
Department of Pathology, Nagoya University Graduate School of Medicine 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Kawai
Kumi
K
Fukihara
Jun
J
Nakamura
Akari
A
Hasegawa
Masaki
M
Suzuki
Chikage
C
Sato
Tomoko
T
Enomoto
Atsushi
A
Asai
Naoya
N
Murakumo
Yoshiki
Y
Takahashi
Masahide
M
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
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