Antagonistic crosstalk of Wnt/β-catenin/Bmp signaling within the Apical Ectodermal Ridge (AER) regulates interdigit formation

Abstract

Digit and interdigit (D/ID) development is one of the important research fields in molecular developmental biology. Interdigital cell death (ICD) is a morphogenetic event which has been considered as an essential process for D/ID formation. Although, some growth factors including Bmp and Fgf signaling can modulate ICD, growth factor crosstalk regulating ICD is poorly understood. Wnt canonical pathway and Bmp signal crosstalk has been considered as the essential growth factor crosstalk in organogenesis. To elucidate the crosstalk to regulate the D/ID formation, we analyzed conditional mutant mice with limb bud ectoderm expressing constitutively activated β-catenin signaling. We showed that modulation of Wnt/β-catenin signal in the limb ectoderm including the AER regulates ID apoptosis. We also demonstrated that Wnt/β-catenin signaling in the ectoderm can positively regulate Fgf8 possibly antagonizing the epithelial derived Bmp signaling. Human birth defects for digit abnormalities have been known to be affected by multiple parameters. Elucidation of the potential mechanisms underlying such D/ID development is an urgent medical issue to be solved. This work would be one of the first studies showing essential growth factor cascades in the D/ID formation.

Cartilage-specific β-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development

“…In tissues of varied origin, BMP and WNT signaling appear to interact with one another to regulate processes involving differentiation and proliferation, and both inhibitory and facilitative relationships have been described between these pathways (44–46). During limb development, the relationship between these two pathways is varied and shown to be important during multiple processes (10, 17, 28, 30, 34, 47–61). Our cartilage-specific genetic manipulations of β-CATENIN have uncovered more examples in which the β-CATENIN and BMP/IHH signaling pathways synergistically regulate multiple aspects of cartilage and bone development.…”

Interdigital cell death function and regulation: New insights on an old programmed cell death model

“…Wnt signaling could also participate in the control of ICD. Overexpression of β‐catenin in the distal ectoderm of transgenic mouse limbs leads to a reduction in ICD (Villacorte et al. 2010).…”

BMP10 inhibited the growth and migration of gastric cancer cells

“…Numerous studies have reported that BMP signaling counteracted Wnt/beta-catenin signaling [22,23]. For example, in the colonic epithelium, BMP signaling inhibited Wnt signaling and regulated cell differentiation [22].…”