Gene Symbol: Hhip
Description: Hedgehog-interacting protein
Alias: Hhip1, hedgehog-interacting protein
Species: mouse
Products:     Hhip

Top Publications

  1. Chuang P, McMahon A. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature. 1999;397:617-21 pubmed
    ..Our findings support a model in which Hip attenuates Hedgehog signalling as a result of binding to Hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any Hedgehog signal. ..
  2. Olsen C, Hsu P, Glienke J, Rubanyi G, Brooks A. Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors. BMC Cancer. 2004;4:43 pubmed
    ..These results suggest that reduced expression of HIP, a naturally occurring Hh pathway antagonist, in tumor neo-vasculature may contribute to increased Hh signaling within the tumor and possibly promote angiogenesis. ..
  3. Clavel C, Grisanti L, Zemla R, Rezza A, Barros R, Sennett R, et al. Sox2 in the dermal papilla niche controls hair growth by fine-tuning BMP signaling in differentiating hair shaft progenitors. Dev Cell. 2012;23:981-94 pubmed publisher
    ..Collectively, our data identify Sox2 as a key regulator of hair growth that controls progenitor migration by fine-tuning BMP-mediated mesenchymal-epithelial crosstalk...
  4. Chuang P, Kawcak T, McMahon A. Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung. Genes Dev. 2003;17:342-7 pubmed
    ..Our studies focused on Hip1 in the lung. Here, a dynamic interaction between Hh and fibroblast growth factor (Fgf) signaling, modulated at least in part by Hip1, controls early lung branching. ..
  5. Kawahira H, Ma N, Tzanakakis E, McMahon A, Chuang P, Hebrok M. Combined activities of hedgehog signaling inhibitors regulate pancreas development. Development. 2003;130:4871-9 pubmed
    ..We have analyzed the function of two hedgehog inhibitors, Hhip and patched 1 (Ptch), during pancreas formation...
  6. Coulombe J, Traiffort E, Loulier K, Faure H, Ruat M. Hedgehog interacting protein in the mature brain: membrane-associated and soluble forms. Mol Cell Neurosci. 2004;25:323-33 pubmed
    b>Hedgehog interacting protein (Hip) is considered as a membrane protein implicated in sequestering the hedgehog (hh) morphogens during embryonic development...
  7. Vokes S, Ji H, McCuine S, Tenzen T, Giles S, Zhong S, et al. Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development. 2007;134:1977-89 pubmed
    ..Together, these approaches provide significant new insights into both tissue-specific and general transcriptional targets in a crucial Shh-mediated patterning process. ..
  8. Sekiguchi H, Ii M, Jujo K, Renault M, Thorne T, Clarke T, et al. Estradiol triggers sonic-hedgehog-induced angiogenesis during peripheral nerve regeneration by downregulating hedgehog-interacting protein. Lab Invest. 2012;92:532-42 pubmed publisher
    ..Collectively, these findings suggest that E2 improves nerve recovery, at least in part, by reducing HIP expression, which subsequently leads to an increase in Shh signaling and Shh-induced angiogenesis. ..
  9. Rutter M, Wang J, Huang Z, Kuliszewski M, Post M. Gli2 influences proliferation in the developing lung through regulation of cyclin expression. Am J Respir Cell Mol Biol. 2010;42:615-25 pubmed publisher
    ..of gli2 resulted in increased Shh pathway activation as evident by increased expression of shh, ptc1, ptc2, smo, hhip, and gli1. Interestingly, we also observed increased expression of gli3 transcripts...

More Information


  1. Higashiyama H, Ozawa A, Sumitomo H, Uemura M, Fujino K, Igarashi H, et al. Embryonic cholecystitis and defective gallbladder contraction in the Sox17-haploinsufficient mouse model of biliary atresia. Development. 2017;144:1906-1917 pubmed publisher
  2. Sennett R, Wang Z, Rezza A, Grisanti L, Roitershtein N, Sicchio C, et al. An Integrated Transcriptome Atlas of Embryonic Hair Follicle Progenitors, Their Niche, and the Developing Skin. Dev Cell. 2015;34:577-91 pubmed publisher
    ..Finally, we share all data in an interactive, searchable companion website. Our study provides an overarching view of signaling within the entire embryonic skin and captures a molecular snapshot of HF progenitors and their niche. ..
  3. Outram S, Varas A, Pepicelli C, Crompton T. Hedgehog signaling regulates differentiation from double-negative to double-positive thymocyte. Immunity. 2000;13:187-97 pubmed
    ..We show that one consequence of pre-TCR signaling is downregulation of Smo, allowing DN thymocytes to proliferate and differentiate. ..
  4. Jenner F, IJpma A, Cleary M, Heijsman D, Narcisi R, van der Spek P, et al. Differential gene expression of the intermediate and outer interzone layers of developing articular cartilage in murine embryos. Stem Cells Dev. 2014;23:1883-98 pubmed publisher
    ..The high representation of genes relevant to chondrocyte hypertrophy and endochondral ossification in the outer interzone suggests that it undergoes endochondral ossification. ..
  5. Ren Y, Cowan R, Migone F, Quirk S. Overactivation of hedgehog signaling alters development of the ovarian vasculature in mice. Biol Reprod. 2012;86:174 pubmed publisher
    ..Expression of transcriptional targets of HH signaling, Gli1, Ptch1, and Hhip, which are used as measures of pathway activity, were elevated during the first several days of life in Amhr2(cre/+)..
  6. Mao J, Kim B, Rajurkar M, Shivdasani R, McMahon A. Hedgehog signaling controls mesenchymal growth in the developing mammalian digestive tract. Development. 2010;137:1721-9 pubmed publisher
    ..Together, these studies provide new insights into tissue interactions underlying mammalian gastrointestinal organogenesis and disease. ..
  7. Gao B, Hu J, Stricker S, Cheung M, Ma G, Law K, et al. A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range. Nature. 2009;458:1196-200 pubmed publisher
    ..Furthermore, we show that in a mouse model that recapitulates the E95K mutation, there is a change in the potency and range of signalling. The mice have digit abnormalities consistent with the human disorder. ..
  8. Ikeda Y, Zabbarova I, Schaefer C, Bushnell D, de Groat W, Kanai A, et al. Fgfr2 is integral for bladder mesenchyme patterning and function. Am J Physiol Renal Physiol. 2017;312:F607-F618 pubmed publisher
    ..i>Fgfr2 is critical for bladder mesenchyme patterning by virtue of its role in modulation of hedgehog signaling. ..
  9. Gritli Linde A, Bei M, Maas R, Zhang X, Linde A, McMahon A. Shh signaling within the dental epithelium is necessary for cell proliferation, growth and polarization. Development. 2002;129:5323-37 pubmed
    ..Furthermore, we provide evidence that Shh signaling between ameloblasts and the overlying stratum intermedium may involve subcellular localization of Patched 2 and Gli1 mRNAs, both of which are targets of Shh signaling in these cells. ..
  10. He X, Zhang L, Chen Y, Remke M, Shih D, Lu F, et al. The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma. Nat Med. 2014;20:1035-42 pubmed publisher
  11. Madison B, Braunstein K, Kuizon E, Portman K, Qiao X, Gumucio D. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development. 2005;132:279-89 pubmed
    ..in intestinal morphogenesis, we generated transgenic mice expressing the pan-hedgehog inhibitor, Hhip (hedgehog interacting protein) in the epithelium...
  12. Regard J, Malhotra D, Gvozdenovic Jeremic J, Josey M, Chen M, Weinstein L, et al. Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat Med. 2013;19:1505-12 pubmed publisher
  13. Holtz A, Peterson K, Nishi Y, Morin S, Song J, Charron F, et al. Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning. Development. 2013;140:3423-34 pubmed publisher
    ..Unique to vertebrates are two additional HH-binding antagonists that are induced by HH signaling, HHIP1 and the PTCH1 homologue PTCH2...
  14. Grisanti L, Rezza A, Clavel C, Sennett R, Rendl M. Enpp2/Autotaxin in dermal papilla precursors is dispensable for hair follicle morphogenesis. J Invest Dermatol. 2013;133:2332-2339 pubmed publisher
    ..We conclude that future coablation of both LPA-producing enzymes or of several LPA receptors may reveal the functional role of LPA signaling during hair follicle morphogenesis. ..
  15. Liao M, Zhao X, Chang S, Lo C, Chenier I, Takano T, et al. AT2 R deficiency mediated podocyte loss via activation of ectopic hedgehog interacting protein (Hhip) gene expression. J Pathol. 2017;243:279-293 pubmed publisher
    ..AT2 R was associated with elevated NADPH oxidase 4 levels, which in turn stimulated ectopic hedgehog interacting protein (Hhip) gene expression in podocytes...
  16. Wainwright E, Svingen T, Ng E, Wicking C, Koopman P. Primary cilia function regulates the length of the embryonic trunk axis and urogenital field in mice. Dev Biol. 2014;395:342-54 pubmed publisher
  17. Hsu S, Zhang X, Yu C, Li Z, Wunder J, Hui C, et al. Kif7 promotes hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu. Development. 2011;138:3791-801 pubmed publisher
    ..Furthermore, Kif7 also inhibits Gli transcriptional activity in the chondrocytes when Sufu function is absent. Therefore, Kif7 regulates the activity of Gli transcription factors through both Sufu-dependent and -independent mechanisms...
  18. Sánchez Camacho C, Bovolenta P. Autonomous and non-autonomous Shh signalling mediate the in vivo growth and guidance of mouse retinal ganglion cell axons. Development. 2008;135:3531-41 pubmed publisher
  19. Agrawal V, Kim D, Kwon Y. Hhip regulates tumor-stroma-mediated upregulation of tumor angiogenesis. Exp Mol Med. 2017;49:e289 pubmed publisher
    ..pathway plays an important role in promoting tumor malignancy via fibroblasts; however, the role of hedgehog interacting protein (hhip; inhibitor of Hh pathway) in tumor growth is poorly understood...
  20. Hoelzl M, Heby Henricson K, Gerling M, Dias J, Kuiper R, Trünkle C, et al. Differential requirement of SUFU in tissue development discovered in a hypomorphic mouse model. Dev Biol. 2017;429:132-146 pubmed publisher
    ..Our data demonstrate that tissue development is differentially affected in response to the reduced SUFU levels, providing novel insight regarding the requirements of different levels of SUFU for proper organogenesis. ..
  21. Shou S, Scott V, Reed C, Hitzemann R, Stadler H. Transcriptome analysis of the murine forelimb and hindlimb autopod. Dev Dyn. 2005;234:74-89 pubmed
    ..05) suggesting that by E 12.5, unique gene combinations are being used during the differentiation of each autopod type. ..
  22. Cobourne M, Miletich I, Sharpe P. Restriction of sonic hedgehog signalling during early tooth development. Development. 2004;131:2875-85 pubmed
    ..Therefore, control of the position of tooth initiation in the mandibular arch involves a combination of Shh signalling at sites where teeth are required and antagonism in regions destined to remain edentulous. ..
  23. Mak K, Kronenberg H, Chuang P, Mackem S, Yang Y. Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development. 2008;135:1947-56 pubmed publisher
    ..In addition, we found that bone morphogenetic protein (Bmp) and Wnt/beta-catenin signaling in the cartilage may both mediate the effect of upregulated Ihh signaling in promoting chondrocyte hypertrophy. ..
  24. Yam P, Kent C, Morin S, Farmer W, Alchini R, Lepelletier L, et al. 14-3-3 proteins regulate a cell-intrinsic switch from sonic hedgehog-mediated commissural axon attraction to repulsion after midline crossing. Neuron. 2012;76:735-49 pubmed publisher
    ..Therefore, we identify a 14-3-3 protein-dependent mechanism for a cell-intrinsic temporal switch in the polarity of axon turning responses. ..
  25. Rice R, Connor E, Rice D. Expression patterns of Hedgehog signalling pathway members during mouse palate development. Gene Expr Patterns. 2006;6:206-12 pubmed
    ..The receptor Ptc1 and a regulator of Hh signalling Hhip1 are expressed in the mesenchyme adjacent to the palatal oral epithelium so that the highest level of transcripts ..
  26. Huang H, Cotton J, Wang Y, Rajurkar M, Zhu L, Lewis B, et al. Specific requirement of Gli transcription factors in Hedgehog-mediated intestinal development. J Biol Chem. 2013;288:17589-96 pubmed publisher
    ..Taken together, our study reveals, for the first time, the distinct roles of Gli proteins in intestine development and suggests SLRPs as novel regulators of smooth muscle cell differentiation. ..
  27. Nieuwenhuis E, Barnfield P, Makino S, Hui C. Epidermal hyperplasia and expansion of the interfollicular stem cell compartment in mutant mice with a C-terminal truncation of Patched1. Dev Biol. 2007;308:547-60 pubmed
    ..Increased expression of regulators of epidermal homeostasis, c-Myc and p63, was also observed in Ptc1(mes/mes) adult skin. These results suggest that the CTD of Ptc1 is involved in regulating epidermal homeostasis in mature skin. ..
  28. Li J, Cui Y, Xu J, Wang Q, Yang X, Li Y, et al. Suppressor of Fused restraint of Hedgehog activity level is critical for osteogenic proliferation and differentiation during calvarial bone development. J Biol Chem. 2017;292:15814-15825 pubmed publisher
  29. Xuan S, Sussel L. GATA4 and GATA6 regulate pancreatic endoderm identity through inhibition of hedgehog signaling. Development. 2016;143:780-6 pubmed publisher
    ..These studies establish the importance of GATA4/6-mediated inhibition of hedgehog signaling as a major mechanism regulating pancreatic endoderm specification during patterning of the gut tube. ..
  30. Lee F, Faivre E, Suzawa M, Lontok E, Ebert D, Cai F, et al. Eliminating SF-1 (NR5A1) sumoylation in vivo results in ectopic hedgehog signaling and disruption of endocrine development. Dev Cell. 2011;21:315-27 pubmed publisher
    ..We conclude that the sumoylation cycle greatly expands the functional capacity of transcription factors such as SF-1 and is leveraged during development to achieve cell-type-specific gene expression in multicellular organisms. ..
  31. Wise T, Pravtcheva D. Oligosyndactylism mice have an inversion of chromosome 8. Genetics. 2004;168:2099-112 pubmed
    ..Further analysis of this mutation will determine if a gene interrupted by the break or a long-range effect of the rearrangement on neighboring genes is responsible for the dominant effects of Os. ..
  32. Tang Y, Swietlicki E, Jiang S, Buhman K, Davidson N, Burkly L, et al. Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1280-8 pubmed
    ..These data indicate that Hh signaling plays a role in adult gut epithelial homeostasis by regulating epithelial cell migration from crypt to villus tip and by enhancing apoptosis. ..
  33. Kim E, Cho S, Shin J, Lee M, Kim K, Jung H. Ihh and Runx2/Runx3 signaling interact to coordinate early chondrogenesis: a mouse model. PLoS ONE. 2013;8:e55296 pubmed publisher
    ..These findings suggested that Ihh signaling plays an important role in chondrocyte proliferation and differentiation via interactions with Runx2 and Runx3. ..
  34. Miao D, Liu H, Plut P, Niu M, Huo R, Goltzman D, et al. Impaired endochondral bone development and osteopenia in Gli2-deficient mice. Exp Cell Res. 2004;294:210-22 pubmed
  35. Xiao X, Tang J, Peng C, Wang Y, Fu L, Qiu Z, et al. Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling. Mol Cell. 2017;66:154-162.e10 pubmed publisher
    ..Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation. ..
  36. Loulier K, Ruat M, Traiffort E. Analysis of hedgehog interacting protein in the brain and its expression in nitric oxide synthase-positive cells. Neuroreport. 2005;16:1959-62 pubmed
    b>Hedgehog interacting protein (Hip) and Patched 1 (Ptc1) regulate the cell responses to the morphogen Sonic Hedgehog (Shh). Here, we compare the relative expression patterns of Shh, Hip and Ptc1 transcripts in the E13.5 mouse brain embryo...
  37. Sigulinsky C, Green E, Clark A, Levine E. Vsx2/Chx10 ensures the correct timing and magnitude of Hedgehog signaling in the mouse retina. Dev Biol. 2008;317:560-75 pubmed publisher
    ..Our results suggest that reduced Hh signaling contributes to the reduced level of RPC proliferation in the orJ retina, thereby revealing a role for Vsx2 in mediating mitogen signaling. ..
  38. Holtz A, Griffiths S, Davis S, Bishop B, Siebold C, Allen B. Secreted HHIP1 interacts with heparan sulfate and regulates Hedgehog ligand localization and function. J Cell Biol. 2015;209:739-57 pubmed publisher
    ..controlled by several ligand-binding antagonists including Patched-1 (PTCH1), PTCH2, and HH-interacting protein 1 (HHIP1), whose collective action is essential for proper HH pathway activity...
  39. Hoffmann A, Yang X, Burnicka Turek O, Bosman J, Ren X, Steimle J, et al. Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation. PLoS Genet. 2014;10:e1004604 pubmed publisher
  40. Lao T, Jiang Z, Yun J, Qiu W, Guo F, Huang C, et al. Hhip haploinsufficiency sensitizes mice to age-related emphysema. Proc Natl Acad Sci U S A. 2016;113:E4681-7 pubmed publisher
    Genetic variants in Hedgehog interacting protein (HHIP) have consistently been associated with the susceptibility to develop chronic obstructive pulmonary disease and pulmonary function levels, including the forced expiratory volume in 1 ..
  41. Lao T, Glass K, Qiu W, Polverino F, Gupta K, Morrow J, et al. Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring. Genome Med. 2015;7:12 pubmed publisher
    The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic ..
  42. Zhulyn O, Nieuwenhuis E, Liu Y, Angers S, Hui C. Ptch2 shares overlapping functions with Ptch1 in Smo regulation and limb development. Dev Biol. 2015;397:191-202 pubmed publisher
  43. Jeong J, McMahon A. Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1. Development. 2005;132:143-54 pubmed
    ..The identification of Hh-interacting protein 1 (Hhip1), a vertebrate-specific feedback antagonist of Hh signaling, raises the possibility of overlapping feedback ..
  44. Berman D, Desai N, Wang X, Karhadkar S, Reynon M, Abate Shen C, et al. Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis. Dev Biol. 2004;267:387-98 pubmed
    ..Taken together, our studies indicate that the initial organogenesis of the prostate proceeds independently of Shh, but that Shh or other Hh ligands may play a role in subsequent events that pattern the prostate. ..
  45. Zhulyn O, Li D, Deimling S, Vakili N, Mo R, Puviindran V, et al. A switch from low to high Shh activity regulates establishment of limb progenitors and signaling centers. Dev Cell. 2014;29:241-9 pubmed publisher
  46. Takenaka K, Kise Y, Miki H. GSK3beta positively regulates Hedgehog signaling through Sufu in mammalian cells. Biochem Biophys Res Commun. 2007;353:501-8 pubmed
    ..These results strongly suggest that GSK3beta phosphorylates Sufu to positively regulate Hedgehog signaling in mammalian cells. ..