Spermatogenesis rescue in a mouse deficient for the ubiquitin ligase SCF{beta}-TrCP by single substrate depletion.
beta-TrCP, the substrate recognition subunit of a Skp1-Cul1-F-box (SCF) ubiquitin ligase, is ubiquitously expressed from two distinct paralogs, targeting many regulatory proteins for proteasomal degradation. We generated inducible beta-TrCP hypomorphic mice and found that they are surprisingly healthy, yet have a severe testicular defect. We show that the two beta-TrCP paralogs have a nonredundant role in spermatogenesis. The testicular defect is tightly associated with cell adhesion failure within the seminiferous tubules and is fully reversible upon beta-TrCP restoration. Remarkably, testicular depletion of a single beta-TrCP substrate, Snail1, rescued the adhesion defect and restored spermatogenesis. Our studies highlight an unexpected functional reserve of this central E3, as well as a bottleneck in a specific tissue: a single substrate whose stabilization is incompatible with testicular differentiation.
Kanarek
Naama
N
The Lautenberg Center for Immunology, Jerusalem, Israel.
Horwitz
Elad
E
Mayan
Inbal
I
Leshets
Michael
M
Cojocaru
Gady
G
Davis
Matti
M
Tsuberi
Ben-Zion
BZ
Pikarsky
Eli
E
Pagano
Michele
M
Ben-Neriah
Yinon
Y
D000818:Animals; D007365:Intercellular Junctions / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D010641:Phenotype; D020033:Protein Isoforms; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics* / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D013091:Spermatogenesis / Q000502:physiology*; D013737:Testis / Q000196:embryology* / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D020033:Protein Isoforms; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D044843:SKP Cullin F-Box Protein Ligases