Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Spatially restricted Hedgehog signalling regulates HGF-induced branching of the adult prostate

Nature Cell Biology volume 16, pages 1135–1145 (2014)Cite this article

Subjects

Abstract

Branching morphogenesis is thought to be governed by epithelial–stromal interactions, but the mechanisms underlying specification of branch location remain largely unknown. Prompted by the striking absence of Hedgehog (Hh) response at the sites of nascent buds in regenerating tubules of the adult prostate, we investigated the role of Hh signalling in adult prostate branching morphogenesis. We find that pathway activity is localized to stromal cells, and that its attenuation by genetic or pharmacologic manipulation leads to increased branching. Decreased pathway activity correlates with increased stromal production of hepatocyte growth factor (Hgf), and we show that Hgf induces epithelial tubule branching. Regulation of Hgf expression by Hh signalling is indirect, mediated by Hh-induced expression of the microRNAs miR-26a and miR-26b, which in turn downregulate expression of Hgf. Prostate tubule branching thus may be initiated from regions of low Hh pathway activity, with implications for the prostatic hyperplasia commonly observed in late adulthood.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Absence of stromal Hh response at the tips of nascent buds.
Figure 2: Reduced Hh pathway activity increases tubulogenesis.
Figure 3: Hh pathway activity in stromal cells leads to reduced Hgf levels.
Figure 4: Hgf induces prostate branching.
Figure 5: Suppression of Hgf response inhibits prostate branching.
Figure 6: Hh pathway downregulates Hgf through miR-26a and miR-26b.
Figure 7: Ihh expression patterns stromal Hh response.
Figure 8: Model of the spatial regulation of branching by Hh and Hgf signalling.

Similar content being viewed by others

References

  1. Shin, K. et al. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature 472, 110–114 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sugimura, Y., Cunha, G. R. & Donjacour, A. A. Morphogenesis of ductal networks in the mouse prostate. Biol. Reprod. 34, 961–971 (1986).

    Article  CAS  PubMed  Google Scholar 

  3. Sugimura, Y., Cunha, G. & Donjacour, A. Morphological and histological study of castration-induced degeneration and androgen-induced regeneration in the mouse prostate. Biol. Reprod. 34, 973–983 (1986).

    Article  CAS  PubMed  Google Scholar 

  4. Paolone, D. R. Benign prostatic hyperplasia. Clin. Geriatr. Med. 26, 223–239 (2010).

    Article  PubMed  Google Scholar 

  5. Berman, D. M. et al. Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis. Dev. Biol. 267, 387–398 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Doles, J. et al. Functional compensation in Hedgehog signaling during mouse prostate development. Dev. Biol. 295, 13–25 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Karhadkar, S. S. et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431, 707–712 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Yu, M. & Bushman, W. Differential stage-dependent regulation of prostatic epithelial morphogenesis by Hedgehog signaling. Dev. Biol. 380, 87–98 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Freestone, S. et al. Sonic hedgehog regulates prostatic growth and epithelial differentiation. Dev. Biol. 264, 352–362 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, B-E. et al. Inhibition of epithelial ductal branching in the prostate by sonic hedgehog is indirectly mediated by stromal cells. J. Biol. Chem. 278, 18506–18513 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Pu, Y., Huang, L. & Prins, G. Sonic hedgehog-patched Gli signaling in the developing rat prostate gland: lobe-specific suppression by neonatal estrogens reduces ductal growth and branching. Dev. Biol. 273, 257–275 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Podlasek, C., Barnett, D., Clemens, J., Bak, P. & Bushman, W. Prostate development requires Sonic hedgehog expressed by the urogenital sinus epithelium. Dev. Biol. 209, 28–39 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Lamm, M. et al. Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Dev. Biol. 249, 349–366 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Peng, Y-C., Levine, C. M., Zahid, S., Wilson, E. L. & Joyner, A. L. Sonic hedgehog signals to multiple prostate stromal stem cells that replenish distinct stromal subtypes during regeneration. Proc. Natl Acad. Sci. USA 110, 20611–20616 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hama, H. et al. Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain. Nat. Neurosci. 14, 1481–1488 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Niranjan, B. et al. HGF/SF: a potent cytokine for mammary growth, morphogenesis and development. Development 121, 2897–2908 (1995).

    CAS  PubMed  Google Scholar 

  17. Soriano, J. V., Pepper, M. S., Nakamura, T., Orci, L. & Montesano, R. Hepatocyte growth factor stimulates extensive development of branching duct-like structures by cloned mammary gland epithelial cells. J. Cell Sci. 108, 413–430 (1995).

    CAS  PubMed  Google Scholar 

  18. Ohmichi, H., Koshimizu, U., Matsumoto, K. & Nakamura, T. Hepatocyte growth factor (HGF) acts as a mesenchyme-derived morphogenic factor during fetal lung development. Development 125, 1315–1324 (1998).

    CAS  PubMed  Google Scholar 

  19. Santos, O. F. P. et al. Involvement of hepatocyte growth factor in kidney development. Dev. Biol. 163, 525–529 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Lukacs, R. U., Goldstein, A. S., Lawson, D. A., Cheng, D. & Witte, O. N. Isolation, cultivation and characterization of adult murine prostate stem cells. Nat. Protoc. 5, 702–713 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stoker, M., Gherardi, E., Perryman, M. & Gray, J. Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327, 239–242 (1987).

    Article  CAS  PubMed  Google Scholar 

  22. Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005–1009 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Montesano, R., Matsumoto, K., Nakamura, T. & Orci, L. Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor. Cell 67, 901–908 (1991).

    Article  CAS  PubMed  Google Scholar 

  24. Montesano, R., Schaller, G. & Orci, L. Induction of epithelial tubular morphogenesis in vitro by fibroblast-derived soluble factors. Cell 66, 697–711 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Lawson, D., Xin, L., Lukacs, R., Cheng, D. & Witte, O. Isolation and functional characterization of murine prostate stem cells. Proc. Natl Acad. Sci. USA 104, 181–186 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Goldstein, A. S. et al. Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristics. Proc. Natl Acad. Sci. USA 105, 20882–20887 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, X. et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461, 495–500 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Huh, C. G. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc. Natl Acad. Sci. USA 101, 4477–4482 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu, L. et al. Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1 H-pyrazole-4-carboxamide (AMG 458). J. Med. Chem. 51, 3688–3691 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Dai, P. et al. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J. Biol. Chem. 274, 8143–8152 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Maragkakis, M. et al. Accurate microRNA target prediction correlates with protein repression levels. BMC Bioinformatics 10, 295–304 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Maragkakis, M. et al. DIANA-microT web server: elucidating microRNA functions through target prediction. Nucleic Acids Res. 37, W273–W276 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Harfe, B. et al. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 118, 517–528 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. McNeal, J. E. Pathology of benign prostatic hyperplasia. Insight into etiology. Urol. Clin. North Am. 17, 477–486 (1990).

    CAS  PubMed  Google Scholar 

  37. McNeal, J. E. Origin and evolution of benign prostatic enlargement. Invest. Urol. 15, 340–345 (1978).

    CAS  PubMed  Google Scholar 

  38. Price, H., McNeal, J. E. & Stamey, T. A. Evolving patterns of tissue composition in benign prostatic hyperplasia as a function of specimen size. Hum. Pathol. 21, 578–585 (1990).

    Article  CAS  PubMed  Google Scholar 

  39. Lee, K. L. & Peehl, D. M. Molecular and cellular pathogenesis of benign prostatic hyperplasia. J. Urol. 172, 1784–1791 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Untergasser, G., Madersbacher, S. & Berger, P. Benign prostatic hyperplasia: age-related tissue-remodeling. Exp. Gerontol. 40, 121–128 (2005).

    Article  PubMed  Google Scholar 

  41. Fan, L. et al. Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 145, 3961–3970 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Pisters, L. L. et al. c-met proto-oncogene expression in benign and malignant human prostate tissues. J. Urol. 154, 293–298 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Nakashiro, K., Okamoto, M., Hayashi, Y. & Oyasu, R. Hepatocyte growth factor secreted by prostate-derived stromal cells stimulates growth of androgen-independent human prostatic carcinoma cells. Am. J. Pathol. 157, 795–803 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bai, C., Auerbach, W., Lee, J., Stephen, D. & Joyner, A. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development 129, 4753–4761 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Ahn, S. & Joyner, A. Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning. Cell 118, 505–516 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L. & Luo, L. A global double-fluorescent Cre reporter mouse. Genesis 45, 593–605 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Long, F., Zhang, X. M., Karp, S., Yang, Y. & McMahon, A. P. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 128, 5099–5108 (2001).

    CAS  PubMed  Google Scholar 

  49. Huang, D. W. et al. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 35, W169–W175 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Robarge, K. et al. GDC-0449–A potent inhibitor of the hedgehog pathway. Bioorg. Med. Chem. Lett. 19, 5576–5581 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported in part by grants from the National Institutes of Health to P.A.B. and a Pathway to Independence Award (K99/R00) to K.S. P.A.B. is an investigator of the Howard Hughes Medical Institute. We acknowledge the Stanford Neuroscience Imaging Facility for use of the two-photon microscope. We thank O. Witte for advice on subrenal prostate regeneration experiments.

Author information

Author notes

  1. Kunyoo Shin

    Present address: Present address: Department of Cell, Developmental, and Cancer Biology, Department of Urology, Oregon Health and Science University School of Medicine, Portland, Oregon 97239, USA.,

  2. Agnes Lim and Kunyoo Shin: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA

    Agnes Lim, Kunyoo Shin, Chen Zhao, Sally Kawano & Philip A. Beachy

  2. Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA

    Agnes Lim & Philip A. Beachy

  3. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA

    Agnes Lim, Kunyoo Shin, Chen Zhao, Sally Kawano & Philip A. Beachy

  4. Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA

    Kunyoo Shin, Chen Zhao & Philip A. Beachy

Authors
  1. Agnes Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kunyoo Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chen Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sally Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Philip A. Beachy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.L., K.S. and P.A.B. conceived ideas and experimental design. A.L. and K.S. performed the experiments. C.Z. assisted with subrenal capsule prostate grafting experiments. S.K. genotyped the animals. A.L., K.S. and P.A.B. wrote the manuscript.

Corresponding authors

Correspondence to Kunyoo Shin or Philip A. Beachy.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Spatial organization of Hh-responsive cells in the prostate and in vivo manipulation of the Hh pathway.

(a) Experimental scheme describing castration and androgen replacement to study prostate regeneration. Tamoxifen (TM) was administered to induce Cre-mediated recombination in Gli1-positive cells during regeneration. (b) Three-dimensional reconstruction of two-photon images of regenerating prostate tubules from Gli1CreER/WT; R26mTmG/WT prostates. Arrowheads indicate the location of a nascent bud, which lacks Gli1-positive cells. Numbers indicate the degree of rotation of the tubule relative to the starting position. Scale bars represent 100 μm. (c) RT-PCR analysis of VP or DLP from vehicle or GDC-0449 (GDC) treated mice showing a decrease in Gli1 expression with GDC treatment. (d) RT-PCR analysis of VP or DLP from oil or TM-treated Gli1CreER/WT; Smofloxflox mice showing a decrease in Gli1 expression with TM treatment. (c, d) n = 3 pairs of VP or DLP per condition. Data are presented as mean ± s.e.m., and significance was calculated by an unpaired Student’s t-test (∗P < 0.05,∗∗P < 0.01).

Supplementary Figure 2 Hh pathway down-regulates Hgf levels in NIH 3T3 cells.

(a) Experimental scheme describing the collection of conditioned media (CM) from NIH 3T3 cells treated with purmorphamine or DMSO (control). MDCK cysts were cultured in CM and analysed after 6 days. (b) Top left: MDCK cyst formed after 7 days in culture. Top right: Formation of extensions after 6 days of culture in control CM. Bottom left: MDCK cyst comprised of a monolayer of cells surrounding a lumen. Intense actin staining at the lumenal surface corresponds to apical microvilli, and cortical actin delineate the basolateral surfaces. Bottom right: Cytoplasmic protrusions, termed extensions, are formed after 6 days in CM. (c) Cysts cultured in CM from NIH 3T3 cells treated with purmorphamine have a significantly decreased frequency of extension formation compared to the DMSO control. The percentage was determined by counting the total number of cysts and cysts with extensions or tubules in 10 random fields of view in each of 4 wells. One representative experiment of three is shown. (d) RT-PCR analysis of NIH 3T3 cells treated with purmorphamine or DMSO. There is an increase in Gli1 mRNA levels and a 1.8-fold decrease in Hgf mRNA levels following purmorphamine treatment compared to control. n = 3 independent samples (RNA extracted from 3 sets of NIH 3T3 cells cultured on separate days). (c, d) Data are presented as mean ± s.e.m., and significance was calculated by an unpaired Student’s t-test (∗P < 0.05,∗∗P < 0.01,∗∗∗∗P < 0.0001).

Supplementary Figure 3 In vivo and in vitro manipulation of Hgf signalling.

(a) Quantification of the total number of cells in each well of primary prostate basal epithelial cells cultured in vitro and treated with recombinant Hgf protein or control (ctrl). n = 3 wells per condition. Treatment with Hgf led to increased cell proliferation (1.9-fold, ∗P < 0.05). Data are presented as mean ± s.e.m., and significance was calculated by an unpaired Student’s t-test. (b) Genotyping of TM-treated mice. Mice harbouring the Actin-CreER allele showed recombination at the c-Met locus, as seen from the band at 650 b.p., which is absent in control mice. (c) Total protein extracts were prepared from the livers of mice after treatment with vehicle (Veh) or AMG 458 (AMG) twice a day for 6 days, and equal amounts of protein was loaded into each well for analysis by Western blotting for phosphorylated c-Met and β-Tubulin. Each lane represents liver extracts from a single mouse, and numbers indicate unique pairs of vehicle or AMG 458 treated mice. Markers of molecular mass are indicated on the left. Numbers above each band indicate the intensity of each phosphorylated c-Met band normalized to the intensity of β-Tubulin band from the same sample.

Supplementary Figure 4 Conservation of miR26a/b target sites in the 3’UTR of Hgf.

(a) Schematic representation of the two predicted miR-26b target sites within the 3′ UTR of Hgf. Vertical lines indicate Watson-Crick pairing. Two nucleotides, complementary to nucleotides 3 and 5 of miR-26b, were mutated in each predicted target site in the Hgf 3′ UTR. The numbers indicate the positions of the nucleotides in the reference wild-type sequence (NM_010427). (b, c) UCSC Genome Browser alignment of 36 vertebrate sequences homologous to the 3′ UTR of murine Hgf, showing conservation of miR26a/b seed region target sequences in both site 1 (b) and site 2 (c).

Supplementary Figure 5 All stromal cells are Hh-pathway responsive.

(a) Experimental scheme to isolate Gli1-positive and negative stromal cells by FACS. (b) RT-PCR analysis of RNA extracted from EYFP-positive and negative stromal cells treated with DMSO or purmorphamine. Both EYFP-positive and negative stromal cells responded to Hh pathway stimulation by upregulating Gli1 expression. n = 3 wells per condition, one representative experiment of three shown. (c) RT-PCR analysis of Shh or Ihh expression in the bladder, prostate or colon. n = 3 technical replicates per sample, one representative experiment of three shown. (d) Primary adult prostate stromal cells in culture were treated with recombinant Ihh protein and RNA extracted 24 h later. Treatment with Ihh lead to increased expression of Gli1, miR-26a and miR-26b and decreased expression of Hgf. n = 4 wells per condition, one representative experiment of three shown. Data are presented as mean ± s.e.m., and significance was calculated by a unpaired Student’s t-test (∗P < 0.05,∗∗P < 0.01,∗∗∗P < 0.001). (e) Prostate and bladder sections from the same ShhCreER/WT; R26mTmG/WT mouse treated with TM. GFP expression was detected in the bladder (right panels) but not in the distal prostate (left panels). Scale bars represent 50 μm. One representative experiment of three is shown.

Supplementary Figure 6 Generation of the IhhCreER mouse strain.

(a) Strategy used to knock the CreER-FRT-Neo-FRT cassette into the Ihh locus. Top: Genomic organization of Ihh represented in a line diagram. Grey boxes represent the exons (numbered accordingly). White boxes represent the untranslated regions. Red lines represent the arms used for homologous recombination. Middle: Targeting vector used for homologous recombination. Bottom: Line drawing representing the allele after homologous recombination. The expected fragment size from NdeI digestion is 12.7 kb for the correctly targeted allele, and 9.3 kb without recombination. ‘SB probe’ indicates location of probe used for Southern blotting. N: NdeI, D: DraI. (b) Southern blotting of genomic DNA from mouse embryonic stem cell (mESC) clones digested with NdeI. WT: wild type. MT: mutant.

Supplementary information

Supplementary Information

Supplementary Information (PDF 858 kb)

Three-dimensional reconstruction of a regenerating prostate tubule.

Three-dimensional reconstruction of two-photon images of a regenerating prostate tubule from a Gli1CreER/WT; R26mTmG/WT mouse prostate. This video corresponds to the images shown in Fig. 1a. (MP4 9890 kb)

Three-dimensional reconstruction of a regenerating prostate tubule.

Three-dimensional reconstruction of two-photon images of a regenerating prostate tubule from a Gli1CreER/WT; R26mTmG/WT mouse prostate. This video corresponds to tubule #2 shown in Supplementary Fig. 1b. (MP4 3362 kb)

Three-dimensional reconstruction of a regenerating prostate tubule.

Three-dimensional reconstruction of two-photon images of a regenerating prostate tubule from a Gli1CreER/WT; R26mTmG/WT mouse prostate. This video corresponds to tubule #3 shown in Supplementary Fig. 1b. (MP4 6134 kb)

Three-dimensional reconstruction of a regenerating prostate tubule.

Three-dimensional reconstruction of two-photon images of a regenerating prostate tubule from a Gli1CreER/WT; R26mTmG/WT mouse prostate. This video corresponds to tubule #4 shown in Supplementary Fig. 1b. (MP4 2673 kb)

Branching induced by treatment of prostate spheres in vitro with Hgf.

Prostate cells harvested from adult R26mTmG mice were cultured in vitro, then treated with Hgf to induce branching. (MP4 2230 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lim, A., Shin, K., Zhao, C. et al. Spatially restricted Hedgehog signalling regulates HGF-induced branching of the adult prostate. Nat Cell Biol 16, 1135–1145 (2014). https://doi.org/10.1038/ncb3057

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb3057

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing