Retinoic acid regulation of the somitogenesis clock - PubMed (original) (raw)

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Retinoic acid regulation of the somitogenesis clock

Gregg Duester. Birth Defects Res C Embryo Today. 2007 Jun.

Abstract

Retinoic acid (RA) is a signaling molecule synthesized from vitamin A that controls gene expression at the transcriptional level by functioning as a ligand for nuclear RA receptors. RA plays an essential role during embryonic development in higher animals by regulating key genes involved in pattern formation. RA is required for induction of several Hox genes involved in patterning of the hindbrain and spinal cord as neuroectoderm emerges from the primitive streak. Recent findings indicate that RA is also required to ensure bilaterally symmetrical generation of left and right somites as presomitic mesoderm emerges from the primitive streak. RA may control somitogenesis through its ability to repress posterior ectodermal expression of fibroblast growth factor-8 (Fgf8) for a short period of time during the late primitive streak stage when the somitogenesis clock initiates. During this tight temporal window, RA is required to limit Fgf8 expression to the most posterior ectoderm (epiblast), thus preventing ectopic Fgf8 expression in more anterior ectoderm including the node ectoderm and neuroectoderm. Although Fgf8 is required for the node to impart left-right asymmetry on specific tissues (heart, visceral organs, etc.), excess Fgf8 signaling following a loss of RA may stimulate the node to generate asymmetry also in presomitic mesoderm, leading to left-right asymmetry in the somitogenesis clock. These findings suggest that human vertebral birth defects such as scoliosis, an abnormal left-right bending of the vertebral column, may be caused by a defect in RA signaling during somitogenesis.

(c) 2007 Wiley-Liss, Inc.

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Figures

Figure 1

Figure 1

RA synthesis pathway. Conversion of vitamin A (retinol) to retinoic acid (RA) requires two sequential oxidation steps. First, retinol is oxidized to retinaldehyde by either alcohol dehydrogenase (ADH) or short-chain dehydrogenase/reductase (SDR). Second, retinaldehyde is oxidized to RA by retinaldehyde dehydrogenase (RALDH). Once synthesized, RA can regulate transcription by serving as a ligand for nuclear RA receptors (RAR), or RA can be further oxidized by P450 enzymes (CYP26) as part of a degradative pathway.

Figure 2

Figure 2

Control of RA signaling by retinoid-binding proteins. Retinol is carried in the bloodstream by serum retinol-binding protein (RBP), which facilitates entry of retinol into cells via a specific receptor. Upon entry, retinol binds cellular RBP (CRBP), which provides a sequestration function. Free retinol is oxidized to RA, some of which can diffuse out of the cell and enter nearby cells by passive diffusion facilitated by cellular RA-binding protein (CRABP), which provides a sequestration function. CRABP can also facilitate transport of RA to the nucleus, and upon dissociation from CRABP, RA can then bind the RA receptor (RAR). In the liganded state, RAR, bound to DNA as a heterodimer with RXR, recruits coactivator proteins that stimulate transcription. The DNA element to which RAR-RXR heterodimers bind is known as a retinoic acid response element (RARE).

Figure 3

Figure 3

Disruption of somite left–right patterning in the absence of RA signaling. Depicted are embryos at the eight-somite stage in which the wild-type embryo has eight pairs of somites whereas the _Raldh2_−/− embryo has eight somites on the left side but only seven somites on the right. Thus, a loss of RA synthesis results in a loss of left–right bilateral symmetry during somite generation; plus, somites are smaller in size along the anteroposterior axis. RA is normally synthesized by Raldh2 expressed in the somites and RA released by somitic mesoderm functions to limit the anterior border of Fgf8 expression in ectodermal epiblast cells along the primitive streak (ps). Somites form in mesoderm just anterior to the Fgf8 expression domain. A loss of RA signaling results in an anterior advance of FGF8 signaling (advancing further on the right than on the left), which may be responsible for both the smaller size of somites and a failure to generate left–right somite pairs in synchrony.

Figure 4

Figure 4

Anterior advance of Fgf8 expression following a loss of RA signaling. Fgf8 expression is normally confined to primitive streak (ps) tissues posterior to the node, a structure that plays a role in gastrulation and left–right patterning of lateral plate mesoderm. RA is first generated by Raldh2 expressed in the presomitic mesoderm (psm) during the late primitive streak stage, when it is required to limit the border of Fgf8 expression to a position just posterior to the node at the anterior end of the primitive streak. A loss of RA allows Fgf8 expression to enter the node and adjacent neuroectoderm (ne), which may lead to excessive FGF8 signaling to mesoderm. Excessive FGF8 signaling in the presomitic mesoderm could result in less cells condensing to form each somite (smaller somites), and excessive FGF8 signaling in the node could impart left–right asymmetry on presomitic mesoderm, which normally does not exhibit such asymmetry.

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