Retinoic acid receptor regulation of decision-making for cell differentiation

Abstract

All-trans retinoic acid (ATRA) activation of retinoic acid receptors (RARs) is crucial to an organism’s proper development as established by findings for mouse foetuses from dams fed a vitamin A-deficient diet. ATRA influences decision-making by embryonic stem (ES) cells for differentiation including lineage fate. From studies of knockout mice, RARα and RARγ regulate haematopoiesis whereby active RARα modulates the frequency of decision-making for myeloid differentiation, but is not essential for myelopoiesis, and active RARγ supports stem cell self-renewal and maintenance. From studies of zebrafish embryo development, active RARγ plays a negative role in stem cell decision-making for differentiation whereby, in the absence of exogenous ATRA, selective agonism of RARγ disrupted stem cell decision-making for differentiation patterning for development. From transactivation studies, 0.24 nM ATRA transactivated RARγ and 19.3 nM (80-fold more) was needed to transactivate RARα. Therefore, the dose of ATRA that cells are exposed to in vivo, from gradients created by cells that synthesize and metabolize, is important to RARγ versus RARα and RARγ activation and balancing of the involvements in modulating stem cell maintenance versus decision-making for differentiation. RARγ activation favours stemness whereas concomitant or temporal activation of RARγ and RARα favours differentiation. Crosstalk with signalling events that are provoked by membrane receptors is also important.

Stemness and Cell Cycle Regulators and Their Modulation by Retinoic Acid in Ewing Sarcoma

“…RA can regulate stem cell phenotype maintenance versus differentiation in ESCs as well as in CSCs [23,26]. In the present study, we found that RA acutely hinders the viability of SK-ES-1 ES cells; increases expression of CDKN1A, p21, and CD99 while reducing expression of SOX2 and TUBB3; and impairs the formation of ES tumorspheres with high expression of SOX2 and Nestin.…”

Pet Wellness and Vitamin A: A Narrative Overview

“…ATRA is recognized for its pivotal involvement in fundamental cellular processes such as growth (including in bones), differentiation, and organogenesis [125,126]. Through its specific binding to the RARs located in target cells, ATRA operates as a transcriptional regulator, modulating the expression of genes crucial for cell differentiation, proliferation, morphogenesis, and tissue development [127][128][129]. This regulatory mechanism orchestrates the intricate process of cell specialization and the formation of distinct tissues and organs during embryonic development [130].…”

SALIQ in Rhabdomyosarcoma: A Repurposed Multidrug Regimen to Augment Standard Treatments by Adding Simvastatin, All Trans Retinoic Acid, Lithium, Itraconazole, and Quercetin

“…Vitamin A is an essential nutrient as animals cannot synthesize it [40]. ATRA drives differentiation in many different cell lineages and settings [41]. It is also used as a pharmaceutical driver of differentiation in pediatric neuroblastoma and pediatric acute promyelocytic leukemia [42][43][44].…”