Abstract
Normal patterning of tissues and organs requires the tight restriction of signaling molecules to well-defined organizing centers. In the limb bud, one of the main signaling centers is the zone of polarizing activity (ZPA) that controls growth and patterning through the production of sonic hedgehog (SHH). The appropriate temporal and spatial expression of Shh is crucial for normal limb bud patterning, because modifications, even if subtle, have important phenotypic consequences. However, although there is a lot of information about the factors that activate and maintain Shh expression, much less is known about the mechanisms that restrict its expression to the ZPA. In this study, we show that BMP activity negatively regulates Shh transcription and that a BMP-Shh negative-feedback loop serves to confine Shh expression. BMP-dependent downregulation of Shh is achieved by interfering with the FGF and Wnt signaling activities that maintain Shh expression. We also show that FGF induction of Shh requires protein synthesis and is mediated by the ERK1/2 MAPK transduction pathway. BMP gene expression in the posterior limb bud mesoderm is positively regulated by FGF signaling and finely regulated by an auto-regulatory loop. Our study emphasizes the intricacy of the crosstalk between the major signaling pathways in the posterior limb bud.
Highlights
The anatomy of the amniote limb is characterized by clear asymmetries in the antero-posterior axis and is well displayed by the different shapes of the digits
Bone morphogenetic proteins (BMP) signaling downregulates Shh expression in the chick zone of polarizing Activity (ZPA) To examine whether Shh expression was under the control of BMP signaling in the ZPA, we experimentally manipulated the level of BMP signaling in the posterior limb mesoderm
The appropriate level of BMP signaling in the posterior limb bud mesoderm is the result of a delicate balance between positive signals (SHH, fibroblast growth factors (FGFs) and Wnt pathways) and counteracting factors
Summary
The anatomy of the amniote limb is characterized by clear asymmetries in the antero-posterior axis and is well displayed by the different shapes of the digits. A multitude of observations and experiments in the past years indicates that the signaling molecule sonic hedgehog (SHH) has a crucial role in specifying the number and identity of the digits by controlling both proliferation and patterning in the developing limb (Bastida and Ros, 2008; McMahon et al, 2003; Towers and Tickle, 2009). SHH is secreted by the zone of polarizing Activity (ZPA), a group of cells located at the posterior margin of the bud (Riddle et al, 1993). The ZPA was originally identified by its capacity to direct antero-posterior patterning; it was later shown that all its properties are due to the production of SHH (Lopez-Martinez et al, 1995; Riddle et al, 1993; Yang et al, 1997). Naturally occurring variations in the intensity or duration of the SHH signal, even if subtle, have been shown to correlate with changes in Instituto de Biomedicina y Biotecnología de Cantabria IBBTEC (CSIC-UC-IDICAN) and Departamento de Anatomía y Biología Celular, Universidad de Cantabria, C/Herrera Oria s/n, E-39011 Santander, Spain
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