TY - JOUR
T1 - Cell-based computational model of early ovarian development in mice
AU - Wear, Hannah M.
AU - Eriksson, Annika
AU - Yao, Humphrey Hung Chang
AU - Watanabe-Sailor, Karen
N1 - Funding Information:
1Institute of Environmental Health, Oregon Health & Science University, Portland, OR, USA;2Division of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University Portland, OR, USA; 3Reproductive Developmental Biology Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA and 4School of Public Health, Oregon Health & Science University, Portland, OR, USA ∗Correspondence: School of Mathematical and Natural Sciences, Arizona State University, 4701 W. Thunderbird Rd., Glendale, AZ 85308-4908, USA. E-mail: Karen.Watanabe@asu.edu †Grant Support: This research was supported by the Alternatives Research and Development Foundation, U.S. Army Environmental Quality and Installations 6.1 Basic Research program contracts WP912HZ-15-A-0044 to H.M.W., W912HZ-15-C-0002 to K.H.W., and NIH Intramural Research Fund (ES102965) to H.H.-C.Y. Opinions, interpretations, Conference Presentation: Presented in part at the following: OHSU Research Week, 4–8 May 2015, Portland, Oregon; 25th Annual Meeting of the Pacific Northwest Chapter of the Society of Environmental Toxicology and Chemistry, 1–4 June 2016, Bellingham, Washington; and at the 49th Annual Meeting of the Society for the Study of Reproduction, 16–20 July 2016, San Diego, California.
Publisher Copyright:
© The Author 2017. Published by Oxford University Press Society for the Study of Reproduction. All rights reserved.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - Despite its importance to reproduction, certain mechanisms of early ovarian development remain a mystery. To improve our understanding, we constructed the first cell-based computational model of ovarian development in mice that is divided into two phases: Phase I spans embryonic day 5.5 (E5.5) to E12.5; and Phase II spans E12.5 to postnatal day 2. We used the model to investigate four mechanisms: in Phase I, (i) whether primordial germ cells (PGCs) undergo mitosis during migration; and (ii) if the mechanism for secretion of KIT ligand from the hindgut resembles inductive cell-cell signaling or is secreted in a static manner; and in Phase II, (iii) that changes in cellular adhesion produce germ cell nest breakdown; and (iv) whether localization of primordial follicles in the cortex of the ovary is due to proliferation of granulosa cells. We found that the combination of the first three hypotheses produced results that aligned with experimental images and PGC abundance data. Results from the fourth hypothesis did not match experimental images, which suggests that more detailed processes are involved in follicle localization. Phase I and Phase II of the model reproduce experimentally observed cell counts and morphology well. A sensitivity analysis identified contact energies, mitotic rates, KIT chemotaxis strength, and diffusion rate in Phase I and oocyte death rate in Phase II as parameters with the greatest impact on model predictions. The results demonstrate that the computational model can be used to understand unknown mechanisms, generate new hypotheses, and serve as an educational tool.
AB - Despite its importance to reproduction, certain mechanisms of early ovarian development remain a mystery. To improve our understanding, we constructed the first cell-based computational model of ovarian development in mice that is divided into two phases: Phase I spans embryonic day 5.5 (E5.5) to E12.5; and Phase II spans E12.5 to postnatal day 2. We used the model to investigate four mechanisms: in Phase I, (i) whether primordial germ cells (PGCs) undergo mitosis during migration; and (ii) if the mechanism for secretion of KIT ligand from the hindgut resembles inductive cell-cell signaling or is secreted in a static manner; and in Phase II, (iii) that changes in cellular adhesion produce germ cell nest breakdown; and (iv) whether localization of primordial follicles in the cortex of the ovary is due to proliferation of granulosa cells. We found that the combination of the first three hypotheses produced results that aligned with experimental images and PGC abundance data. Results from the fourth hypothesis did not match experimental images, which suggests that more detailed processes are involved in follicle localization. Phase I and Phase II of the model reproduce experimentally observed cell counts and morphology well. A sensitivity analysis identified contact energies, mitotic rates, KIT chemotaxis strength, and diffusion rate in Phase I and oocyte death rate in Phase II as parameters with the greatest impact on model predictions. The results demonstrate that the computational model can be used to understand unknown mechanisms, generate new hypotheses, and serve as an educational tool.
KW - Cell-based model
KW - Computational model
KW - Developmental biology
KW - Mice
KW - Ovarian development
KW - Ovary
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U2 - 10.1093/biolre/iox089
DO - 10.1093/biolre/iox089
M3 - Article
C2 - 29088396
AN - SCOPUS:85044663821
SN - 0006-3363
VL - 97
SP - 365
EP - 377
JO - Biology of Reproduction
JF - Biology of Reproduction
IS - 3
ER -