RARβ2 is required for vertebrate somitogenesis

Abstract

During vertebrate somitogenesis, retinoic acid is known to establish the position of the determination wavefront, controlling where new somites are permitted to form along the anteroposterior body axis. Less is understood about how RAR regulates somite patterning, rostral-caudal boundary setting, specialization of myotome subdivisions or the specific RAR subtype that is required for somite patterning. Characterizing the function of RARβ has been challenging due to the absence of embryonic phenotypes in murine loss-offunction studies. Using the Xenopus system, we show that RARβ2 plays a specific role in somite number and size, restriction of the presomitic mesoderm anterior border, somite chevron morphology and hypaxial myoblast migration. Rarβ2 is the RAR subtype whose expression is most upregulated in response to ligand and its localization in the trunk somites positions it at the right time and place to respond to embryonic retinoid levels during somitogenesis. RARβ2 positively regulates Tbx3 a marker of hypaxial muscle, and negatively regulates Tbx6 via Ripply2 to restrict the anterior boundaries of the presomitic mesoderm and caudal progenitor pool. These results demonstrate for the first time an early and essential role for RARβ2 in vertebrate somitogenesis.

Inverse agonism of retinoic acid receptors directs epiblast cells into the paraxial mesoderm lineage

“…4D). Further, this likely explains why the highest expression levels and percentage of cells with Tbx6 reporter activity were present in the E*M* treated cultures as it is known that Tbx6 expression decreases during paraxial mesoderm maturation(Janesick et al, 2017). …”

New Insights into the Control of Cell Fate Choices and Differentiation by Retinoic Acid in Cranial, Axial and Caudal Structures

“…MPC (T/Bra + /Msgn1 + /Tbx6 + ) express Aldh1a2, leading to enhanced RA production, which diffuses to the surrounding tissue and results in repression of T/Bra and activation of Sox2 in NPC and, therefore, to neural differentiation. Figure modified from [68,[70][71][72][73][74]. Additional abbreviations: PS, primitive streak; PNT, pre-neural tube.…”

“…This is the receptor subtype most strongly downregulated by pan-RAR inverse agonist AGN193109 and correspondingly upregulated in response to a treatment with the pan-RAR agonist TTNPB. Initiation or maintenance of rarβ2 expression is dependent on Rarα/γ, as a knockdown of either of those two receptors causes the loss of rarβ2 expression [73]. In Xenopus, this RA receptor is active in mature somites and its loss leads to the rostral expansion of unsegmented PSM markers (tbx6, msgn, fgf8) and also shifts the expression domains of somitomere markers (ripply2, mespa) rostrally.…”

“…As a result, fewer but larger somites develop that lack distinct boundaries and chevron morphology. Therefore, in Xenopus, RA activates Rarβ2 in the trunk to regulate somitogenesis, while rarγ2 is expressed in the RA free tail area, sustaining the PSM and NMP cell population [72,73] ( Figure 1B).…”

“…In tetrapods, the skeletal elements of the vertebral bodies develop from sclerotome-derived cells by endochondral ossification [72][73][74]. In contrast, vertebral bodies of teleosts develop through intramembranous ossification in two steps.…”