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Author Notes:

Corresponding Author: Eric J. Sorscher, M.D., Emory University, 1760 Haygood Drive, Suite 280, Atlanta, GA 30322. Phone: (404) 727-3293. esorscher@emory.edu

Subjects:

Research Funding:

Funding for this project was provided by CFF SORSCH R464 and NIH P30 DK072482.

This manuscript also represents contribution number 18–606-J from the Kansas Agricultural Experiment Station.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Developmental Biology
  • TRANSMEMBRANE CONDUCTANCE REGULATOR
  • CONGENITAL BILATERAL ABSENCE
  • ANION SECRETION
  • CFTR
  • EXPRESSION
  • GENE
  • DIFFERENTIATION
  • MUTATIONS
  • PHENOTYPE
  • CATENIN

Non-obstructive vas deferens and epididymis loss in cystic fibrosis rats

Journal Title:

MECHANISMS OF DEVELOPMENT

Volume:

Volume 155

Publisher:

, Pages 15-26

Type of Work:

Article | Post-print: After Peer Review

Abstract:

This study utilizes morphological and mechanistic endpoints to characterize the onset of bilateral atresia of the vas deferens in a recently derived cystic fibrosis (CF) rat model. Embryonic reproductive structures, including Wolffian (mesonephric) duct, Mullerian (paramesonephric) duct, mesonephric tubules, and gonad, were shown to mature normally through late embryogenesis, with involution of the vas deferens and/or epididymis typically occurring between birth and postnatal day 4 (P4), although timing and degree of atresia varied. No evidence of mucus obstruction, which is associated with pathology in other CF-affected tissues, was observed at any embryological or postnatal time point. Reduced epididymal coiling was noted post-partum and appeared to coincide with, or predate, loss of more distal vas deferens structure. Remarkably, α smooth muscle actin expression in cells surrounding duct epithelia was markedly diminished in CF animals by P2.5 when compared to wild type counterparts, indicating reduced muscle development. RNA-seq and immunohistochemical analysis of affected tissues showed disruption of developmental signaling by Wnt and related pathways. The findings have relevance to vas deferens loss in humans with CF, where timing of ductular damage is not well characterized and underlying mechanisms are not understood. If vas deferens atresia in humans begins in late gestation and continues through early postnatal life, emerging modulator therapies given perinatally might preserve and enhance integrity of the reproductive tract, which is otherwise absent or deficient in 97% of males with cystic fibrosis.

Copyright information:

© 2018 Elsevier B.V.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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