Conserved regulation of proximodistal limb axis development by Meis1/Hth

Abstract

Vertebrate limbs grow out from the flanks of embryos, with their main axis extending proximodistally from the trunk. Distinct limb domains, each with specific traits, are generated in a proximal-to-distal sequence during development. Diffusible factors expressed from signalling centres promote the outgrowth of limbs and specify their dorsoventral and anteroposterior axes. However, the molecular mechanism by which limb cells acquire their proximodistal (P-D) identity is unknown. Here we describe the role of the homeobox genes Meis1/2 and Pbx1 in the development of mouse, chicken and Drosophila limbs. We find that Meis1/2 expression is restricted to a proximal domain, coincident with the previously reported domain in which Pbx1 is localized to the nucleus, and resembling the distribution of the Drosophila homologues homothorax (hth) and extradenticle (exd); that Meis1 regulates Pbx1 activity by promoting nuclear import of the Pbx1 protein; and that ectopic expression of Meis1 in chicken and hth in Drosophila disrupts distal limb development and induces distal-to-proximal transformations. We suggest that restriction of Meis1/Hth to proximal regions of the vertebrate and insect limb is essential to specify cell fates and differentiation patterns along the P-D axis of the limb.

Retinoic Acid Synthesis Controlled by Raldh2 Is Required Early for Limb Bud Initiation and Then Later as a Proximodistal Signal during Apical Ectodermal Ridge Formation

“…Meis2 encodes a homeobox transcription factor expressed in the lateral plate mesoderm and subsequently in the proximal limb mesoderm that is required as a determinant of proximal limb identity (31). In E9.0 Raldh2 Ϫ/Ϫ embryos we found that Meis2 expression was not detected in the lateral plate mesoderm and somites as normal but was still present in the hindbrain ( Fig.…”

Expression of key retinoic acid modulating genes suggests active regulation during development and regeneration of the amphibian limb

“…RA has also been proposed to control proximal to distal patterning of the limb via direct regulation of the proximally expressed Meis homeodomain proteins, Meis1 and Meis2 (Mercader et al, 2000(Mercader et al, , 2005. Overexpression of these genes leads to truncation of the distal limb (Capdevila et al, 1999;Mercader et al, 1999). Targeted disruption of Meis1 results in death at around embryonic day 14.5 in mice (Hisa et al, 2004;Azcoitia et al, 2005).…”

Identification of E74-like factor 1 (ELF1) as a transcriptional regulator of the Hox cofactor MEIS1

“…Key roles of this transcription factor are now documented both in normal development and disease formation (1)(2)(3)(4). Decreased MEIS1 levels are associated with Restless leg syndrome (RLS) (5,6).…”

“…Decreased MEIS1 levels are associated with Restless leg syndrome (RLS) (5,6). Overexpression of MEIS1, on the other hand, has been linked to leukemia (3,4).…”