Nodal signaling regulates germ cell development and establishment of seminiferous cords in the human fetal testis

Anne Jorgensen; Joni Macdonald; John E. Nielsen; Karen R. Kilcoyne; Signe Perlman; Lene Lundvall; Lea Langhoff Thuesen; Kristine Juul Hare; Hanne Frederiksen; Anna-Maria Andersson; Niels E. Skakkebaek; Anders Juul; Richard M. Sharpe; Ewa Rajpert-De Meyts; Rod T. Mitchell

doi:10.1016/j.celrep.2018.10.064

Nodal signaling regulates germ cell development and establishment of seminiferous cords in the human fetal testis

Anne Jorgensen^*, Joni Macdonald, John E. Nielsen, Karen R. Kilcoyne, Signe Perlman, Lene Lundvall, Lea Langhoff Thuesen, Kristine Juul Hare, Hanne Frederiksen, Anna-Maria Andersson, Niels E. Skakkebaek, Anders Juul, Richard M. Sharpe, Ewa Rajpert-De Meyts, Rod T. Mitchell

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1924-1937.e4
Number of pages	18
Journal	Cell Reports
Volume	25
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2018.10.064
Publication status	Published - 13 Nov 2018

Keywords / Materials (for Non-textual outputs)

CARCINOMA-IN-SITU
GONADAL DEVELOPMENT
TESTICULAR CANCER
SOMATIC-CELLS
EXPRESSION
MEIOSIS
MARKERS
TUMORS
DIFFERENTIATION
XENOGRAFTS

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10.1016/j.celrep.2018.10.064Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

Mitchell R Nodal Signalling Regulates...
Cell Reports 25, 1924–1937, November 13, 2018ª2018 The Author(s). This is an open access article under the CC BY-NC-ND license
Final published version, 8.93 MBLicence: CC BY-NC-ND

Rod Mitchell
- Deanery of Clinical Sciences - Personal Chair of Developmental Endocrinology
- Centre for Reproductive Health
Person: Academic: Research Active

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Jorgensen, A., Macdonald, J., Nielsen, J. E., Kilcoyne, K. R., Perlman, S., Lundvall, L., Thuesen, L. L., Hare, K. J., Frederiksen, H., Andersson, A.-M., Skakkebaek, N. E., Juul, A., Sharpe, R. M., Rajpert-De Meyts, E., & Mitchell, R. T. (2018). Nodal signaling regulates germ cell development and establishment of seminiferous cords in the human fetal testis. Cell Reports, 25(7), 1924-1937.e4. https://doi.org/10.1016/j.celrep.2018.10.064

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abstract = "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.",

keywords = "CARCINOMA-IN-SITU, GONADAL DEVELOPMENT, TESTICULAR CANCER, SOMATIC-CELLS, EXPRESSION, MEIOSIS, MARKERS, TUMORS, DIFFERENTIATION, XENOGRAFTS",

author = "Anne Jorgensen and Joni Macdonald and Nielsen, {John E.} and Kilcoyne, {Karen R.} and Signe Perlman and Lene Lundvall and Thuesen, {Lea Langhoff} and Hare, {Kristine Juul} and Hanne Frederiksen and Anna-Maria Andersson and Skakkebaek, {Niels E.} and Anders Juul and Sharpe, {Richard M.} and {Rajpert-De Meyts}, Ewa and Mitchell, {Rod T.}",

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doi = "10.1016/j.celrep.2018.10.064",

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Jorgensen, A, Macdonald, J, Nielsen, JE, Kilcoyne, KR, Perlman, S, Lundvall, L, Thuesen, LL, Hare, KJ, Frederiksen, H, Andersson, A-M, Skakkebaek, NE, Juul, A, Sharpe, RM, Rajpert-De Meyts, E & Mitchell, RT 2018, 'Nodal signaling regulates germ cell development and establishment of seminiferous cords in the human fetal testis', Cell Reports, vol. 25, no. 7, pp. 1924-1937.e4. https://doi.org/10.1016/j.celrep.2018.10.064

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T1 - Nodal signaling regulates germ cell development and establishment of seminiferous cords in the human fetal testis

AU - Jorgensen, Anne

AU - Macdonald, Joni

AU - Nielsen, John E.

AU - Kilcoyne, Karen R.

AU - Perlman, Signe

AU - Lundvall, Lene

AU - Thuesen, Lea Langhoff

AU - Hare, Kristine Juul

AU - Frederiksen, Hanne

AU - Andersson, Anna-Maria

AU - Skakkebaek, Niels E.

AU - Juul, Anders

AU - Sharpe, Richard M.

AU - Rajpert-De Meyts, Ewa

AU - Mitchell, Rod T.

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.

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.

KW - CARCINOMA-IN-SITU

KW - GONADAL DEVELOPMENT

KW - TESTICULAR CANCER

KW - SOMATIC-CELLS

KW - EXPRESSION

KW - MEIOSIS

KW - MARKERS

KW - TUMORS

KW - DIFFERENTIATION

KW - XENOGRAFTS

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DO - 10.1016/j.celrep.2018.10.064

M3 - Article

SN - 2211-1247

VL - 25

SP - 1924-1937.e4

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -

Nodal signaling regulates germ cell development and establishment of seminiferous cords in the human fetal testis

Abstract

Keywords / Materials (for Non-textual outputs)

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Rod Mitchell

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