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Front Cell Dev Biol 2021 Jan 01;9:747969. doi: 10.3389/fcell.2021.747969.
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Retinoic Acid Fluctuation Activates an Uneven, Direction-Dependent Network-Wide Robustness Response in Early Embryogenesis.

Parihar M , Bendelac-Kapon L , Gur M , Abbou T , Belorkar A , Achanta S , Kinberg K , Vadigepalli R , Fainsod A .

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.

PubMed ID: 34746144
Article link: Front Cell Dev Biol

Species referenced: Xenopus laevis
Genes referenced: adhfe1 aldh1a2 aldh1a3 crabp2 cyp26a1 cyp26c1 dhrs3 gapdh hoxa1 hoxb1 hoxb4 hoxd1 hoxd4 rbp1 rdh10 rdh13 rdh14 sdr16c5 slc35b1
GO keywords: embryo development [+]

GEO Series: GSE154399: NCBI
GSE154407: NCBI
GSE154408: NCBI

Article Images: [+] show captions
References [+] :
Adams, The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis. 2014, Pubmed