ABSTRACT
Robustness is a characteristic 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 exogenous chemicals. We performed transient physiological RA signaling disturbances during embryogenesis followed by kinetic transcriptomic and high-throughput qPCR analysis of the recovery. Unbiased pattern analysis identified the RA metabolic network as the main regulated module aimed at achieving signaling robustness. We used a principal trajectory-based analysis of the clutch-dependent variability and organized the results into a robustness efficiency matrix comparing the RA feedback regulation and hox gene expression (RA targets). We found the feedback autoregulation to be sensitive to the direction of the RA perturbation: RA knockdown exhibited an upper response threshold, whereas RA addition did not activate a feedback response below a minimum threshold. These results demonstrate an asymmetric capacity for robust feedback control of the RA signal during early embryogenesis, probably based on genetic polymorphisms, likely a significant contributor to the manifestation of developmental defects.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Review Codes for online datasets GEO SuperSeries GSE154408: cryfqygubnszryt https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154408
Revised abstract, introduction, results, and discussion. Updated figures and supplemental files.
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154408
Abbreviations Used
- COMPACT
- Comparative Matrix of Pattern Counts
- DEAB
- 4-diethylaminobenzaldehyde
- PCA
- Principal Component Analysis
- PCR
- Polymerase Chain Reaction
- RA
- retinoic acid
- WGCNA
- Weighted Gene Coexpression Network Analysis