Cooperation of BMP and IHH signaling in interdigital cell fate determination

The elaborate anatomy of hands and feet is shaped by coordinated formation of digits and regression of the interdigital mesenchyme (IM).

A failure of this process causes persistence of interdigital webbing and consequently cutaneous syndactyly.

Bone morphogenetic proteins (BMPs) are key inductive factors for interdigital cell death (ICD) in vivo.

NOGGIN (NOG) is a major BMP antagonist that can interfere with BMP-induced ICD when applied exogenously, but its in vivo role in this process is unknown.

We investigated the physiological role of NOG in ICD and found that Noggin null mice display cutaneous syndactyly and impaired interdigital mesenchyme specification.

Failure of webbing regression was caused by lack of cell cycle exit and interdigital apoptosis.

Unexpectedly, Noggin null mutants also exhibit increased Indian hedgehog (Ihh) expression within cartilage condensations that leads to aberrant extension of IHH downstream signaling into the interdigital mesenchyme.

A converse phenotype with increased apoptosis and reduced cell proliferation was found in the interdigital mesenchyme of Ihh mutant embryos.

Our data point towards a novel role for NOG in balancing Ihh expression in the digits impinging on digit-interdigit cross talk.

This suggests a so far unrecognized physiological role for IHH in interdigital webbing biology.

Programmed cell death is a biological process essential for progressive sculpting and structuring of the developing autopod.

Controlled cell death is evident in marked areas of the limb mesenchyme, primarily the anterior apoptotic zone (AAZ), posterior apoptotic zone (PAZ) and the interdigital apoptotic zone (IAZ).

During the development of digits, the undifferentiated interdigital mesenchyme (IM) undergoes cell cycle withdrawal, senescence and apoptosis, which is crucial for individualization of digits and differential digit elongation.

Concomitantly, the initial digit condensations form and elongate by local recruitment of mesenchymal progenitors to a cartilage fate through elevated SMAD-dependent BMP signaling in antagonism with Wnt/β-catenin signaling.

In summary, this study argues that syndactyly in Noggin null embryos is directly caused by an intrinsic defect in interdigital mesenchyme cell fate regarding cell cycle withdrawal and apoptosis induction, but is not secondary to ectopic chondrogenesis.

Opposing effects on interdigital apoptosis and proliferation in Nog and Ihh mutants support the view that IHH signaling from the condensation may have a direct role in regulating interdigital cell fate and that the upregulation of IHH signaling in Noggin mutants is causative for the defect in interdigit regression.