Expression regulation and function of heparan sulfate 6-O-endosulfatases in the spermatogonial stem cell niche.
Glial cell line-derived neurotrophic factor (GDNF) is a heparan sulfate (HS)-binding factor. GDNF is produced by somatic Sertoli cells, where it signals to maintain spermatogonial stem cells (SSCs) and reproduction. Here, we investigate the roles of extracellular HS 6-O-endosulfatases (Sulfs), Sulf1 and Sulf2, in the matrix transmission of GDNF from Sertoli cells to SSCs. Although Sulfs are not required for testis formation, Sulf deficiency leads to the accelerated depletion of SSCs, a testis phenotype similar to that of GDNF+/- mice. Mechanistically, we show that Sulfs are expressed in GDNF-producing Sertoli cells. In addition, reduced Sulf activity profoundly worsens haplo-deficient GDNF phenotypes in our genetic studies. These findings establish a critical role of Sulfs in promoting GDNF signaling and support a model in which Sulfs regulate the bioavailability of GDNF by enzymatically remodeling HS 6-O-desulfation to release GDNF from matrix sequestration. Further, Sertoli cell-specific transcriptional factor Wilm's tumor 1 (WT1) directly activates the transcription of both Sulf1 and Sulf2 genes. Together, our studies not only identify Sulfs as essential regulators of GDNF signaling in the SSC niche, but also as direct downstream targets of WT1, thus establishing a physiological role of WT1 in Sertoli cells.
Langsdorf
Aliete
A
The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Schumacher
Valerie
V
Shi
Xiaofeng
X
Tran
Thanh
T
Zaia
Joseph
J
Jain
Sanjay
S
Taglienti
Mary
M
Kreidberg
Jordan A
JA
Fine
Alan
A
Ai
Xingbin
X
D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology; D005786:Gene Expression Regulation; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000072260:RNA Splicing Factors; D051381:Rats; D012708:Sertoli Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013093:Spermatogonia / Q000378:metabolism; D055153:Stem Cell Niche / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D013429:Sulfatases / Q000235:genetics / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006497:Heparan Sulfate; D009687:Nuclear Proteins; D000072260:RNA Splicing Factors; D013429:Sulfatases; D015238:Sulfotransferases; C419554:WTAP protein, human; C486773:Sulf1 protein, mouse; C514911:Sulf2 protein, mouse