Role of Retinoic Acid Signaling, FGF Signaling and Meis Genes in Control of Limb Development

Abstract

The function of retinoic acid (RA) during limb development is still debated, as loss and gain of function studies led to opposite conclusions. With regard to limb initiation, genetic studies demonstrated that activation of FGF10 signaling is required for the emergence of limb buds from the trunk, with Tbx5 and RA signaling acting upstream in the forelimb field, whereas Tbx4 and Pitx1 act upstream in the hindlimb field. Early studies in chick embryos suggested that RA as well as Meis1 and Meis2 (Meis1/2) are required for subsequent proximodistal patterning of both forelimbs and hindlimbs, with RA diffusing from the trunk, functioning to activate Meis1/2 specifically in the proximal limb bud mesoderm. However, genetic loss of RA signaling does not result in loss of limb Meis1/2 expression and limb patterning is normal, although Meis1/2 expression is reduced in trunk somitic mesoderm. More recent studies demonstrated that global genetic loss of Meis1/2 results in a somite defect and failure of limb bud initiation. Other new studies reported that conditional genetic loss of Meis1/2 in the limb results in proximodistal patterning defects, and distal FGF8 signaling represses Meis1/2 to constrain its expression to the proximal limb. In this review, we hypothesize that RA and Meis1/2 both function in the trunk to initiate forelimb bud initiation, but that limb Meis1/2 expression is activated proximally by a factor other than RA and repressed distally by FGF8 to generate proximodistal patterning.

Dlx1/2-dependent expression of Meis2 promotes neuronal fate determination in the mammalian striatum

“…Meis2 regulates genes involved in retinoic acid production in the LGE SVZ Retinoic acid (RA), a small molecule derived from vitamin A, is a ligand for nuclear RA receptors, and has been proposed to play important roles in striatal neurogenesis (Berenguer and Duester, 2021;Chatzi et al, 2011;Liao et al, 2008;Oulad-Abdelghani et al, 1997;Toresson et al, 1999;Urban et al, 2010;Waclaw et al, 2004). RA is synthesized by Raldh3 (Aldh1a3) in LGE progenitors at E12.5 (Molotkova et al, 2007;Toresson et al, 1999), and the Gsx2 TF is required for Aldh1a3 expression (Waclaw et al, 2004).…”

Deriving time-concordant event cascades from gene expression data: A case study for Drug-Induced Liver Injury (DILI)

“…Furthermore, it was previously found that artificially increased expression of Hnf4a is able to reverse hepatic liver failure in rats, while also restoring expression of a highly interconnected TF network including Hnf1a and Cebpa which supports the identified interactions [ 65 , 66 ]. Two of the yet unknown TFs in DILI are Meis Homeobox 1 (Meis1) and Meis Homeobox 2 (Meis2) which are generally known in a developmental context [ 67 , 68 ]. However, their down-regulation in early pathogenesis is supported by enriched TF activity, differential expression before adverse histopathology as well as upstream regulators which are also enriched before adverse histopathology.…”

The role of fibroblast growth factor 8 in cartilage development and disease

“…FGF‐8 is involved in the process of cartilage generation, which is mediated by the interaction between FGF‐8 and FGFR, especially FGFR1 and FGFR3. The effect is determined to the difference in signalling pathway strength; FGFR1 mainly regulates catabolism, while FGFR3 mainly regulates anabolism 5,8,49–51 . FGFR3 is expressed in proliferating chondrocytes.…”

“…These results suggest that the classical Wnt signalling pathway exerts a negative feedback effect on regulating the proliferation and differentiation of FGF‐8‐stimulated chondrocytes. Wnt‐mTOR and NF‐κβ also produce acid‐sensing ion channels 1A (ASIC1A) under acidic conditions to promote the apoptosis of chondrocytes 49,50,83,84 …”