BMPs are direct triggers of interdigital programmed cell death

Area of Science:

• Developmental Biology
• Cell Biology
• Genetics

Background:

• Programmed cell death (PCD) removes interdigital mesenchyme during vertebrate embryogenesis, except in species with webbed limbs.
• Bone morphogenetic proteins (BMPs) are implicated in PCD, but their direct role in interdigital mesenchyme versus indirect effects via fibroblast growth factor (FGF) signaling remains debated.

Purpose of the Study:

• To investigate whether BMPs directly trigger PCD in the interdigital mesenchyme.
• To elucidate the specific roles of Bmp2, Bmp4, and Bmp7 in interdigital PCD.
• To determine the necessity of BMP signaling for interdigital vasculature formation.

Main Methods:

• Utilized an interdigit-specific Cre line to inactivate BMP signaling pathway components in mouse embryos.
• Assessed the impact of gene inactivation on PCD, syndactyly, and FGF activity.
• Examined the roles of individual Bmps (Bmp7, Bmp2, Bmp4) and the BMP receptor (Bmpr1a) in PCD.

Main Results:

• Bmp7 is essential for interdigital PCD, while Bmp2 and Bmp4 play redundant roles, with Bmp2 being more significant.
• Inactivation of the BMP receptor gene Bmpr1a resulted in loss of PCD and syndactyly, confirming BMPs as direct triggers.
• Interdigital vasculature formation, necessary for PCD, is independent of BMP and FGF signaling.
• Both BMP and FGF signaling converge on reactive oxygen species production to activate PCD.

Conclusions:

• BMPs directly trigger programmed cell death in the interdigital mesenchyme, essential for normal limb development.
• A model is proposed where BMP-mediated cell death signals and FGF-mediated cell survival signals interact to regulate interdigital PCD.
• The findings clarify the direct role of BMP signaling in limb patterning and PCD.