Nodal Signaling Regulates Germ Cell Development and Establishment of Seminiferous Cords in the Human Fetal Testis

TY - JOUR

T1 - Nodal Signaling Regulates Germ Cell Development and Establishment of Seminiferous Cords in the Human Fetal Testis

AU - Jørgensen, Anne

AU - Macdonald, Joni

AU - Nielsen, John E

AU - Kilcoyne, Karen R

AU - Perlman, Signe

AU - Lundvall, Lene

AU - Langhoff Thuesen, Lea

AU - Juul Hare, Kristine

AU - Frederiksen, Hanne

AU - Andersson, Anna-Maria

AU - Skakkebæk, Niels E

AU - Juul, Anders

AU - Sharpe, Richard M

AU - Rajpert-De Meyts, Ewa

AU - Mitchell, Rod T

N1 - Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2018/11/13

Y1 - 2018/11/13

N2 - Disruption of human fetal testis development is widely accepted to underlie testicular germ cell cancer (TGCC) origin and additional disorders within testicular dysgenesis syndrome (TDS). However, the mechanisms for the development of testicular dysgenesis in humans are unclear. We used ex vivo culture and xenograft approaches to investigate the importance of Nodal and Activin signaling in human fetal testis development. Inhibition of Nodal, and to some extent Activin, signaling disrupted seminiferous cord formation, abolished AMH expression, reduced androgen secretion, and decreased gonocyte numbers. Subsequent xenografting of testicular tissue rescued the disruptive effects on seminiferous cords and somatic cells but not germ cell effects. Stimulation of Nodal signaling increased the number of germ cells expressing pluripotency factors, and these persisted after xenografting. Our findings suggest a key role for Nodal signaling in the regulation of gonocyte differentiation and early human testis development with implications for the understanding of TGCC and TDS origin. Jørgensen et al. determine the role of Nodal signaling in human fetal testis development using ex vivo culture and xenografting approaches. They provide insights into the involvement of Nodal signaling in seminiferous cord formation and the regulation of pluripotency factor expression in fetal gonocytes, with implications for the development of testicular cancer.

AB - Disruption of human fetal testis development is widely accepted to underlie testicular germ cell cancer (TGCC) origin and additional disorders within testicular dysgenesis syndrome (TDS). However, the mechanisms for the development of testicular dysgenesis in humans are unclear. We used ex vivo culture and xenograft approaches to investigate the importance of Nodal and Activin signaling in human fetal testis development. Inhibition of Nodal, and to some extent Activin, signaling disrupted seminiferous cord formation, abolished AMH expression, reduced androgen secretion, and decreased gonocyte numbers. Subsequent xenografting of testicular tissue rescued the disruptive effects on seminiferous cords and somatic cells but not germ cell effects. Stimulation of Nodal signaling increased the number of germ cells expressing pluripotency factors, and these persisted after xenografting. Our findings suggest a key role for Nodal signaling in the regulation of gonocyte differentiation and early human testis development with implications for the understanding of TGCC and TDS origin. Jørgensen et al. determine the role of Nodal signaling in human fetal testis development using ex vivo culture and xenografting approaches. They provide insights into the involvement of Nodal signaling in seminiferous cord formation and the regulation of pluripotency factor expression in fetal gonocytes, with implications for the development of testicular cancer.

U2 - 10.1016/j.celrep.2018.10.064

DO - 10.1016/j.celrep.2018.10.064

M3 - Journal article

C2 - 30428358

SN - 2211-1247

VL - 25

SP - 1924-1937.e4

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -