retinoic acid

Definition: Retinoic acid is the oxidized form of Vitamin A.

Functions

Embryology

Retinoic acid via the retinoic acid receptor influences the process of cell differentiation, hence, the growth and development of embryos.

Retinoic acid functions in determining position along embryonic anterior/posterior axis in chordates. It acts through Hox genes, which ultimately controls anterior/posterior patterning in early developmental stages.

Retinoic acid acts by binding to heterodimers of the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), which then bind to retinoic acid response elements (RAREs) in the regulatory regions of direct targets (including Hox genes), thereby activating gene transcription.

Retinoic acid receptors mediate transcription of different sets of genes of cell differentiation, thus it also depends on the target cells. One of the target genes is the gene of the retinoic acid receptor itself which occurs during positive regulation. Control of retinoic acid levels is maintained by a suite of proteins.

During development there is a concentration gradient of retinoic acid along the anterior-posterior (head-tail) axis.

Cells in the embryo respond differently to retinoic acid depending on the amount present. For example, in vertebrates the hindbrain transiently forms eight rhombomers and each rhombomere has a specific pattern of genes being expressed.

If retinoic acid is not present the last four rhombomeres do not develop. Instead rhombomeres 1-4 grow to cover the same amount of space as all eight would normally occupy.

Retinoic acid has its effects by turning on a differential pattern of Hox genes which encode different homeodomain transcription factors which in turn can turn on cell type specific genes.

Deletion of the Hox-1 gene from rhombomere 4 makes the neurons growing in that region behave like neurons from rhombomere 2. The retina is also patterned by retinoic acid, with a concentration gradient that is high on the ventral side of the retina and low on the dorsal side.

The molecular basis for the interaction between retinoic acid and the Hox genes has been studied by using deletion analysis in transgenic mice carrying constructs of lacZ reporter genes.

Such studies have identified functional RAREs within flanking sequences of some of the most 3’ Hox genes, suggesting a direct interaction between the genes and retinoic acid.

These types of studies strongly support the normal roles of retinoids in patterning vertebrate embryogenesis through the Hox genes.

Stem cell biology

Retinoic acid is an influential factor used in differentiation of stem cells to more committed fates, echoing retinoic acid’s importance in natural embryonic developmental pathways.

It is thought to initiate differentiation into a number of different cell lineages by unsequestering certain sequences in the genome.

It has numerous applications in a plethora of stem cell differentiation protocols; amongst these are the differentiation of human embryonic stem cells to posterior foregut lineages and also to functional motor neurons.

Pathology

 In vertebrates and amphioxus, excess retinoic acid severely perturbs embryonic development.

See also

 RARs

• RARA

References

 Niederreither K, Dollé P. Retinoic acid in development: towards an integrated view. Nat Rev Genet. 2008 Jun 10. PMID: 18542081

 Mark M, Ghyselinck NB, Chambon P. Retinoic acid signalling in the development of branchial arches. Curr Opin Genet Dev. 2004 Oct;14(5):591-8. PMID: 15380252