Patched 1 and Patched 2 Redundancy Has a Key Role in Regulating Epidermal Differentiation

Abstract

The Patched 1 (Ptch1) receptor has a pivotal role in inhibiting the activity of the Hedgehog (Hh) pathway and is therefore critical in preventing the onset of many human developmental disorders and tumor formation. However, the functional role of the mammalian Ptch2 paralogue remains elusive, particularly the extent to which it contributes to regulating the spatial and temporal activity of Hh signaling. Here we demonstrate in three independent mouse models of epidermal development that in vivo ablation of both Ptch receptors results in a more severe phenotype than loss of Ptch1 alone. Our studies indicate that concomitant loss of Ptch1 and Ptch2 activity inhibits epidermal lineage specification and differentiation. These results reveal that repression of Hh signaling through a dynamic Ptch regulatory network is a crucial event in lineage fate determination in the skin. In general, our findings implicate Ptch receptor redundancy as a key issue in elucidating the cellular origin of Hh-induced tumors.

Patched Receptors Sense, Interpret, and Establish an Epidermal Hedgehog Signaling Gradient

“…We recently proposed that the difference in outcome between a tumorigenic Ptch1-deficient phenotype and the loss of epidermal specification and differentiation observed in Ptch1;Ptch2-deficient skin is attributable to differences in the amplitude of Hh signalling activity subsequently evoking distinct cellular responses (Adolphe et al, 2014). In order to define the amplitude of pathway activity we used single molecule fluorescent in situ hybridization (smFISH) to quantitate RNA transcript density of the Hh target genes Ptch1 and Gli1 in individual cells (Figure 1a) (Junker et al, 2014;Raj et al, 2008).…”

“…Thus the level of activity generated in Ptch1-deficient cells acts to define the tumorigenic threshold of Hh signalling in skin. In contrast, we have recently shown that concomitant inactivation of both Ptch1 and Ptch2 during epidermal development leads to loss of interfollicular epidermis (IFE), HF and sebaceous gland specification and differentiation (Adolphe et al, 2014). Taken together, these data indicate that different amplitudes of Hh signalling activity drive distinct cellular responses and cell fate decisions in the skin.…”

“…K5Cre, Ptch1 and Ptch2 mice have been previously described (Adolphe et al, 2014) and experiments performed according to the University of Queensland animal ethics guidelines.…”

Mechanism of Hair Loss from the Point of View of Epidermal Cell Polarity

“…To overcome this problem, two groups, including my group, generated mutant mice with epidermis-specific loss of aPKCλ using K5-Cre or K14-Cre mice [22,23]. Although, in a strict sense, the distribution of K14-Cre transgene activity differs from that of K5-Cre transgene activity in the epidermis and hair follicle [25,26], both mutant mice showed similar skin phenotypes. Thus, hereafter, when referring to findings common to both conditional knockout (cKO) mice, the term mutant mice or aPKCλ cKO mice is used, and when referring to findings obtained in the mutant mice associated with K5-Cre or K14-Cre individually, the term K5-cKO or K14-cKO mice is used, respectively.…”

Secreted HHIP1 interacts with heparan sulfate and regulates Hedgehog ligand localization and function

“…In vertebrates, HH-dependent patterning requires not only PTCH1, but two additional, vertebrate-specific feedback antagonists: the PTCH1 homologue, PTCH2, and HHIP1 (Motoyama et al, 1998;Carpenter et al, 1998;Chuang and McMahon, 1999;Koudijs et al, 2005Koudijs et al, , 2008. PTCH1 and PTCH2 act redundantly in multiple cells and tissues, including the developing skin (Adolphe et al, 2014;Alfaro et al, 2014). However, HH-dependent ventral neural patterning is severely disrupted after the combined removal of PTCH2, HHIP1, and PTCH1 feedback inhibition (Milenkovic et al, 1999;Jeong and McMahon, 2005;Holtz et al, 2013).…”