Program in Molecular Medicine, University of Massachusetts Medical School, Biotech II, Suite 213, 373 Plantation Street, Worcester, MA 01605, USA.
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Dev Cell. 2014 Nov 10;31(3):279-290. doi: 10.1016/j.devcel.2014.09.011. Epub 2014 Oct 30.
Vertebrate hedgehog signaling is coordinated by the differential localization of the receptors patched-1 and Smoothened in the primary cilium. Cilia assembly is mediated by intraflagellar transport (IFT), and cilia defects disrupt hedgehog signaling, causing many structural birth defects. We generated Ift25 and Ift27 knockout mice and show that they have structural birth defects indicative of hedgehog signaling dysfunction. Surprisingly, ciliary assembly is not affected, but abnormal hedgehog signaling is observed in conjunction with ciliary accumulation of patched-1 and Smoothened. Similarly, Smoothened accumulates in cilia on cells mutated for BBSome components or the BBS binding protein/regulator Lztfl1. Interestingly, the BBSome and Lztfl1 accumulate to high levels in Ift27 mutant cilia. Because Lztfl1 mutant cells accumulate BBSome but not IFT27, it is likely that Lztfl1 functions downstream of IFT27 to couple the BBSome to the IFT particle for coordinated removal of patched-1 and Smoothened from cilia during hedgehog signaling.
脊椎动物 hedgehog 信号传导是通过受体 patched-1 和 Smoothened 在初级纤毛中的差异定位来协调的。纤毛组装由内鞭毛运输 (IFT) 介导，纤毛缺陷破坏 hedgehog 信号传导，导致许多结构出生缺陷。我们生成了 Ift25 和 Ift27 敲除小鼠，并表明它们具有指示 hedgehog 信号传导功能障碍的结构出生缺陷。令人惊讶的是，纤毛组装不受影响，但观察到 patched-1 和 Smoothened 的纤毛积累伴随着异常的 hedgehog 信号传导。同样，Smoothened 在 BBSome 成分或 BBS 结合蛋白/调节剂 Lztfl1 突变细胞的纤毛中积累。有趣的是，BBSome 和 Lztfl1 在 Ift27 突变纤毛中积累到高水平。因为 Lztfl1 突变细胞积累 BBSome 但不积累 IFT27，所以 Lztfl1 可能在 IFT27 下游发挥作用，将 BBSome 与 IFT 颗粒偶联，以便在 hedgehog 信号传导期间将 patched-1 和 Smoothened 从纤毛中协调去除。
