Retinoic Acid Fluctuation Activates an Uneven, Direction-Dependent Network-Wide Robustness Response in Early Embryogenesis

Madhur Parihar, Liat Bendelac-Kapon, Michal Gur, Tali Abbou, Abha Belorkar, Sirisha Achanta, Keren Kinberg, Rajanikanth Vadigepalli*, Abraham Fainsod*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Robustness is a feature of regulatory pathways to ensure signal consistency in light of environmental changes or genetic polymorphisms. The retinoic acid (RA) pathway, is a central developmental and tissue homeostasis regulatory signal, strongly dependent on nutritional sources of retinoids and affected by environmental chemicals. This pathway is characterized by multiple proteins or enzymes capable of performing each step and their integration into a self-regulating network. We studied RA network robustness by transient physiological RA signaling disturbances followed by kinetic transcriptomic analysis of the recovery during embryogenesis. The RA metabolic network was identified as the main regulated module to achieve signaling robustness using an unbiased pattern analysis. We describe the network-wide responses to RA signal manipulation and found the feedback autoregulation to be sensitive to the direction of the RA perturbation: RA knockdown exhibited an upper response limit, whereas RA addition had a minimal feedback-activation threshold. Surprisingly, our robustness response analysis suggests that the RA metabolic network regulation exhibits a multi-objective optimization, known as Pareto optimization, characterized by trade-offs between competing functionalities. We observe that efficient robustness to increasing RA is accompanied by worsening robustness to reduced RA levels and vice versa. This direction-dependent trade-off in the network-wide feedback response, results in an uneven robustness capacity of the RA network during early embryogenesis, likely a significant contributor to the manifestation of developmental defects.

Original languageAmerican English
Article number747969
JournalFrontiers in Cell and Developmental Biology
StatePublished - 20 Oct 2021

Bibliographical note

Funding Information:
RV acknowledged the financial support for this project from the National Institute of Biomedical Imaging and Bioengineering grant U01 EB023224 and from the Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University. AF acknowledged the financial support from the Israel Science Foundation (grant 668/17), the Manitoba Liquor and Lotteries (grant RG-003-21), and the Wolfson Family Chair in Genetics. RV and AF acknowledged the Pilot Funding grant from Thomas Jefferson University and The Hebrew University of Jerusalem collaborative research program.

Publisher Copyright:
© Copyright © 2021 Parihar, Bendelac-Kapon, Gur, Abbou, Belorkar, Achanta, Kinberg, Vadigepalli and Fainsod.


  • Pareto optimization
  • Xenopus embryo
  • autoregulatory feedback control
  • developmental trajectory analysis
  • embryo development
  • retinoic acid
  • temporal gene expression pattern analysis
  • time-series transcriptomics


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