Dual Roles for Patched in Sequestering and Transducing Hedgehog

Abstract

Secreted proteins of the Hedgehog (Hh) family have diverse organizing roles in animal development. Recently, a serpentine protein Smoothened (Smo) has been proposed as a Hh receptor. Here, we present evidence that implicates another multiple-pass transmembrane protein, Patched (Ptc), in Hh reception and suggests a novel signal transduction mechanism in which Hh binds to Ptc, or a Ptc-Smo complex, and thereby induces Smo activity. Our results also show that Ptc limits the range of Hh action; we provide evidence that high levels of Ptc induced by Hh serve to sequester any free Hh and therefore create a barrier to its further movement.

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

“…Reduced binding to PTC1 is a contributing factor because the sequestering of IHH by cells close to the source was reduced [8,35], which would allow the mutant IHH to diffuse farther. This effect was also a compounding effect as the subsequent induction of Ptc1 expression was reduced because of the impaired signaling [27].…”

“…Binding to PTC1 is thought to be one of the processes regulating Hh movement and gradient formation [8,35]. Previously, we have shown a potential change in the IHH gradient in the developing growth plate in homozygous Ihh E95K/E95K BDA1 mice using in situ hybridization analysis of downstream Hh targets, including Ptc1 and Gli1 [27].…”

Regulation of Hedgehog signaling: a complex story

“…The Hh ligands, Sonic, Indian and Desert Hh in vertebrates and Hh in Drosophila, signal through binding to the membrane receptor Patched (Ptc) [2][3][4], to reverse the Ptc-mediated inhibition of signaling by the trans-membrane protein Smoothened (Smo) [5]. This allows Smo to activate the intracellular signaling components, resulting in stabilization of down-stream transcriptional activator(s) and activation of target genes [3,[5][6][7].…”

“…This is achieved primarily through internalization of Hhbound Ptc into endocytic vesicles [35,40]. Binding of Hh to Ptc also functions to limit the range of Hh signaling, as Ptc expressing cells near the A/P boundary can sequester Hh and prevent its diffusion far into the anterior [4].…”

Uncovering the uncharacterized and unexpected: Unbiased phenotype‐driven screens in the mouse

“…The phenotypes of Smoothened bnb (Smo bnb ) and Dispatched1 icb (Disp1 icb ) appear to represent loss of all activity of the vertebrate Hedgehog pathways, and these strong phenotypes facilitated their identification in our screen for embryos that display a morphological defect at midgestation (Caspary et al, 2002). In Drosophila, there is a large maternal contribution of smo and disp, and null phenotypes are seen only when both maternal and zygotic components are removed (Alcedo et al, 1996;Chen and Struhl, 1996;van den Heuvel and Ingham, 1996;Burke et al, 1999;Amanai and Jiang, 2001). Similarly, there is a substantial maternal contribution of Smo and Disp1 in zebrafish, which may account for the weaker phenotype of zebrafish Smo and disp1 mutants Nagai et al, 2000;Varga et al, 2001;Nakano et al, 2004) than mouse Smo and disp1 mutants (Zhang et al, 2001;Caspary et al, 2002;Kawakami et al, 2002;Ma et al, 2002).…”