RT Journal Article
T1 A dominant negative mutation uncovers cooperative control of caudal Wolffian duct development by Sprouty genes.
A1 Altés, Gisela
A1 Vaquero, Marta
A1 Cuesta, Sara
A1 Anerillas, Carlos
A1 Macià, Anna
A1 Espinet, Carme
A1 Ribera, Joan
A1 Bellusci, Saverio
A1 Klein, Ophir D
A1 Yeramian, Andree
A1 Dolcet, Xavi
A1 Egea, Joaquim
A1 Encinas, Mario
K1 Dominant negative
K1 Gartner cyst
K1 Genitourinary development
K1 Seminal vesicle
K1 Wolffian duct
AB The Wolffian ducts (WD) are paired epithelial tubules central to the development of the mammalian genitourinary tract. Outgrowths from the WD known as the ureteric buds (UB) generate the collecting ducts of the kidney. Later during development, the caudal portion of the WD will form the vas deferens, epididymis and seminal vesicle in males, and will degenerate in females. While the genetic pathways controlling the development of the UB are firmly established, less is known about those governing development of WD portions caudal to the UB. Sprouty proteins are inhibitors of receptor tyrosine kinase (RTK) signaling in vivo. We have recently shown that homozygous mutation of a conserved tyrosine (Tyr53) of Spry1 results in UB defects indistinguishable from that of Spry1 null mice. Here, we show that heterozygosity for the Spry1 Y53A allele causes caudal WD developmental defects consisting of ectopically branched seminal vesicles in males and persistent WD in females, without affecting kidney development. Detailed analysis reveals that this phenotype also occurs in Spry1+/- mice but with a much lower penetrance, indicating that removal of tyrosine 53 generates a dominant negative mutation in vivo. Supporting this notion, concomitant deletion of one allele of Spry1 and Spry2 also recapitulates the genital phenotype of Spry1Y53A/+ mice with high penetrance. Mechanistically, we show that unlike the effects of Spry1 in kidney development, these caudal WD defects are independent of Ret signaling, but can be completely rescued by lowering the genetic dosage of Fgf10. In conclusion, mutation of tyrosine 53 of Spry1 generates a dominant negative allele that uncovers fine-tuning of caudal WD development by Sprouty genes.
YR 2022
FD 2022-09-13
LK http://hdl.handle.net/10668/19531
UL http://hdl.handle.net/10668/19531
LA en
DS RISalud
RD Apr 7, 2025