Proximo-distal positional information encoded by an Fgf-regulated gradient of homeodomain transcription factors in the vertebrate limb

Abstract

The positional information theory proposes that a coordinate system provides information to embryonic cells about their position and orientation along a patterning axis. Cells interpret this information to produce the appropriate pattern. During development, morphogens and interpreter transcription factors provide this information. We report a gradient of Meis homeodomain transcription factors along the mouse limb bud proximo-distal (PD) axis antiparallel to and shaped by the inhibitory action of distal fibroblast growth factor (FGF). Elimination of Meis results in premature limb distalization and HoxA expression, proximalization of PD segmental borders, and phocomelia. Our results show that Meis transcription factors interpret FGF signaling to convey positional information along the limb bud PD axis. These findings establish a new model for the generation of PD identities in the vertebrate limb and provide a molecular basis for the interpretation of FGF signal gradients during axial patterning.

Axial skeleton anterior-posterior patterning is regulated through feedback regulation between Meis transcription factors and retinoic acid

“…Studies in zebrafish (Choe et al, 2014) and mouse (Amin et al, 2015) embryos indeed showed that some of these binding sites represent Hox auto-regulatory elements active in the neural tube and Hox transcription regulation by MEIS factors has been demonstrated in neural tube patterning (Dibner et al, 2001;Vlachakis et al, 2001;Waskiewicz et al, 2001). MEIS elimination or overexpression also affects Hox gene expression during limb skeletal patterning (Delgado et al, 2020;Mercader et al, 1999;Mercader et al, 2009;Rosello-Diez et al, 2014), however, this aspect has not been studied in axial skeleton patterning.…”

Expression of Fibroblast Growth Factor 4 in a Rat Model of Polydactyly of the Thumb Induced by Cytarabine

“…In recent years, research on the molecular mechanism of congenital limb deformity has intensified. The importance of the fibroblast growth factor family in limb development is well known, but the specific role of its various factors in the family and its mechanism of action have not been fully studied [ 22 , 23 ]. A study showed that FGF4 plays an important role in early embryonic development.…”

Establishing the pattern of the vertebrate limb

“…Therefore, proximal structures are lost in Meis1 and Meis2 mutants because of the precocious activation of the 5′-most Hox genes. However, Hoxa11 and then Hoxa13 are still progressively activated in the absence of Meis function (Delgado et al, 2020), which suggests that a timing mechanism underlies this transition (Fig. 5).…”

“…The authors explain these results in terms of an instructive model in which the Fgf to RA ratio is interpreted into a gradient of Meis1 and Meis2 abundance that specifies proximo-distal positional values: high Meis1 and Meis2 would specify proximal positional values, low Meis1 and Meis2, intermediate positional values and absent Meis1 and Meis2, distal positional values (Fig. 5) (Delgado et al, 2020). The diminishing levels of RA, Meis1 and Meis2 would allow the progressive activation of Hoxa11 to Hoxa13.…”

“…Retinoic acid is also likely to coordinate the outgrowth of the limb with proximo-distal patterning, because it needs to be cleared from the early chick wing bud by a combination of active degradation and displacement by growth to allow the programme of 5′ Hoxa/d11-13 gene expression to be activated (Rosello-Diez et al, 2014). Recent evidence from the mouse obtained by the conditional inactivation of Meis1 and Meis2 has been presented in support of the two-signal model (Delgado et al, 2020). The absence of Meis function results in the loss or severe reduction of proximal structures in both forelimbs and hindlimbs, which have normal digit development.…”