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.

手足精细的解剖结构由指（趾）的协同形成与指间间充质（interdigital mesenchyme, IM）的退化共同塑造。若该过程出现异常，将导致指间蹼残留，进而引发皮肤型并指。骨形态发生蛋白（Bone morphogenetic proteins, BMPs）是体内介导指间细胞死亡（interdigital cell death, ICD）的关键诱导因子。Noggin（NOG）是主要的BMP拮抗剂，外源性施加时可干扰BMP诱导的ICD，但其在该过程中的体内生理功能尚不明确。本研究探究了NOG在ICD中的生理作用，发现Noggin敲除小鼠会表现出皮肤型并指与指间间充质特化受损的表型。指间蹼退化失败的原因在于细胞周期退出受阻以及指间细胞凋亡的缺失。出乎意料的是，Noggin敲除突变体的软骨凝聚体中印度刺猬因子（Indian hedgehog, Ihh）表达上调，这导致IHH下游信号通路异常延伸至指间间充质。而在Ihh突变胚胎的指间间充质中，则观察到细胞凋亡增加与细胞增殖降低的相反表型。我们的研究数据表明，NOG在平衡指（趾）组织中Ihh的表达、调控指-指间交互信号对话方面发挥了全新的作用。这提示IHH在指间蹼发育生物学中存在此前未被认知的生理功能。