Retinoic acid receptor regulation of decision-making for cell differentiation

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, RARa and RAR? regulate haematopoiesis whereby active RARa modulates the frequency of decision-making for myeloid differentiation, but is not essential for myelopoiesis, and active RAR? supports stem cell self-renewal and maintenance. From studies of zebrafish embryo development, active RAR? plays a negative role in stem cell decision-making for differentiation whereby, in the absence of exogenous ATRA, selective agonism of RAR? disrupted stem cell decision-making for differentiation patterning for development. From transactivation studies, 0.24 nM ATRA transactivated RAR? and 19.3 nM (80-fold more) was needed to transactivate RARa. Therefore, the dose of ATRA that cells are exposed to in vivo, from gradients created by cells that synthesize and metabolize, is important to RAR? versus RARa and RAR? activation and balancing of the involvements in modulating stem cell maintenance versus decision-making for differentiation. RAR? activation favours stemness whereas concomitant or temporal activation of RAR? and RARa favours differentiation. Crosstalk with signalling events that are provoked by membrane receptors is also important.

Automated summary

The activation of ATRA and RARs is crucial for proper development and decision-making of embryonic stem cells. RARa and RAR? have different roles in regulating hematopoiesis and stem cell maintenance, and their activation is influenced by the dose of ATRA and crosstalk with signaling events.