Señalización Sonic Hedgehog (SHH) en el cerebro adulto: vía crucial para la reactivación de los astrocitos y la reparación del cerebro

  • Olga M. Bermúdez-Muñoz Universidad de Antioquia
Palabras clave: astrocito, daño cerebral, glía, reparación tisular, señalización Hedgehog


Mientras que las neuronas juegan un papel fundamental en la neurotransmisión en el sistema nervioso central de los animales, las células gliales son cruciales para dar sostén a las neuronas y por lo tanto, para el funcionamiento del cerebro. Estudios recientes han puesto de manifiesto que las células gliales regulan la liberación y reciclaje de neurotransmisores, el metabolismo del piruvato y del glutatión, sirviendo de tampón para diferentes iones, participando en la organización de la barrera hematoencefálica y en la producción de mielina y del líquido cefalorraquídeo. La actividad de las células gliales se encuentra estrechamente coordinada por la comunicación entre las neuronas y la glía. Entre la señalización celular del cerebro, la vía Sonic Hedgehog (SHH) juega un papel importante al regular el desarrollo y patrón del sistema nervioso central. En el cerebro adulto, la proteína SHH es secretada por las neuronas y por los astrocitos y media de esa manera las interacciones neuro-gliales. Cuando ocurre un daño en el cerebro,
la vía de señalización SHH es (re)-activada en el cerebro adulto. Las células gliales y particularmente los astrocitos, son células esenciales para la respuesta del cerebro frente a un daño y para su reparación. La respuesta de los astrocitos se encuentra mediada por la activación de la vía SHH en estas células. En este
artículo se revisa la importancia de las células gliales y específicamente de los astrocitos en la fisiología del cerebro, la implicación de la vía de señalización SHH en la organización y funcionamiento del cerebro, y cómo la señalización SHH regula la re-activación de los astrocitos y la respuesta celular frente al daño
tisular y a la reparación del cerebro en el organismo adulto.

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Aberger F, Ruiz I, Altaba A. 2014. Context-dependent signal

integration by the GLI code: the oncogenic load, pathways, modifiers

and implications for cancer therapy. Seminars in Cell and Developmental Biology, 33: 93-104.

Allen NJ. 2013. Role of glia in developmental synapse formation. Current Opinion in Neurobiology, 23: 1027-1033.

Alvarez JI, Dodelet-Devillers A, Kebir H, Ifergan I, Fabre PJ, Terouz S, Sabbagh M, Wosik K, Bourbonnière L, Bernard M, van Horssen J, de Vries HE, Charron F, Prat A. 2011. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science, 334: 1727-1731.

Alvarez JI, Katayama T, Prat A. 2013. Glial influence on the blood brain barrier. Glia, 61: 1939-1958.

Álvarez-Buylla A, Ihrie RA. 2014. Sonic hedgehog signaling in the postnatal brain. Seminars in Cell and Developmental Biology, 33: 105-111.

Araújo GLL, Araújo JAM, Schroeder T, Tort ABL, Costa MR. 2014. Sonic hedgehog signaling regulates mode of cell division of early cerebral cortex progenitors and increases astrogliogenesis. Frontiers in Cellular Neuroscience, 8: 77.

Bachoo RM, Kim RS, Ligon KL, Maher EA, Brennan C, Billings N, Chan S, Li C, Rowitch DH, Wong WH, DePinho RA. Molecular diversity of astrocytes with implications for neurological disorders. 2004. Proceedings of the National Academy of Sciences of the United States of America, 101: 8384-8389.

Bardehle S, Krüger M, Buggenthin F, Schwausch J, Ninkovic J, Clevers H, Snippert HJ, Theis FJ, Meyer-Luehmann M, Bechmann I, Dimou L, Götz M. 2013. Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nature Neuroscience, 16: 580-586.

Barres BA. 1999. A new role for glia: generation of neurons! Cell, 97: 667-670.

Barres BA. 2008. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron, 60: 430-440.

Bayraktar OA, Fuentealba LC, Alvarez-Buylla A, Rowitch DH. 2015. Astrocyte development and heterogeneity. Cold Spring Harbor Perspectives in Biology [Internet], 7: a020362. Accessed: 25 September 2015. Available from: <http://cshperspectives.cshlp. org/content/7/1/a020362>.

Ben Achour S, Pascual O. 2010. Glia: the many ways to modulate synaptic plasticity. Neurochemistry International, 57: 440-445. Briscoe J, Thérond PP. 2013. The mechanisms of Hedgehog signalling and its roles in development and disease. Nature Reviews. Molecular Cell Biology, 14: 416-429.

Campbell K, Götz M. 2002. Radial glia: multi-purpose cells for vertebrate brain development. Trends in Neurosciences, 25: 235-238.

Chaboub LS, Deneen B. 2012. Developmental origins of astrocyte heterogeneity: the final frontier of CNS development. Developmental Neuroscience, 34: 379-388.

Chan WY, Kohsaka S, Rezaie P. 2007. The origin and cell lineage of microglia: new concepts. Brain Research Reviews, 53: 344-354. Cheslow L, Alvarez JI. 2016. Glial-endothelial crosstalk regulates blood-brain barrier function. Current Opinion in Pharmacology, 26: 39-46.

Chotard C, Salecker I. 2004. Neurons and glia: team players in axon guidance. Trends in Neuroscience, 27: 655-661.

Chung W-S, Welsh CA, Barres BA, Stevens B. 2015. Do glia drive synaptic and cognitive impairment in disease? Nature Neuroscience, 18: 1539-1545.

Dimou L, Götz M. 2014. Glial cells as progenitors and stem cells: new roles in the healthy and diseased brain. Physiolical Reviews, 94: 709-737.

Elsayed M, Magistretti PJ. 2015. A New Outlook on Mental Illnesses: Glial Involvement Beyond the Glue. Frontiers in Cellular Neuroscience, 9: 468.

Eroglu C, Barres BA. 2010. Regulation of synaptic connectivity by glia. Nature, 468: 223-231.

Eshed-Eisenbach Y, Peles E. 2013. The making of a node: a co- production of neurons and glia. Current Opinion in Neurobiology,

: 1049-1056.

Fields RD, Burnstock G. 2006. Purinergic signalling in neuron-glia interactions. Nature Reviews Neuroscience, 7: 423-436.

Fleming JT, He W, Hao C, Ketova T, Pan FC, Wright CCV, Litingtung Y, Chiang C. 2013. The Purkinje neuron acts as a central regulator of spatially and functionally distinct cerebellar precursors. Developmental Cell, 27: 278-292.

Gorojankina T. 2016. Hedgehog signaling pathway: a novel model and molecular mechanisms of signal transduction. Cellular and Molecular Life Sciences [Internet]: 1-16. Accessed: 20 November 2015. Available on: < Fs00018-015-2127-4>.

Guerrero I, Kornberg TB. 2014. Hedgehog and its circuitous journey from producing to target cells. Seminars in Cell & Developmental Biology, 33: 52-62.

Han Y-G, Spassky N, Romaguera-Ros M, Garcia-Verdugo J-M, Aguilar A, Schneider-Maunoury S, Alvarez-Buylla A. 2008. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nature Neuroscience, 11: 277-284.

Haydon PG. 2001. GLIA: listening and talking to the synapse. Nature Reviews Neuroscience, 2: 185-193.

Hochstim C, Deneen B, Lukaszewicz A, Zhou Q, Anderson DJ. 2008. Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code. Cell, 133: 510-522.

Huangfu D, Anderson KV. 2005. Cilia and Hedgehog responsiveness in the mouse. Proceedings of the National Academy of Sciences of the United States of America, 102: 11325-11330.

Ihrie RA, Shah JK, Harwell CC, Levine JH, Guinto CD, Lezameta M, Kriegstein AR, Alvarez-Buylla A. 2011. Persistent sonic hedgehog

signaling in adult brain determines neural stem cell positional identity. Neuron, 71: 250-262.

Ingham PW, Nakano Y, Seger C. 2011. Mechanisms and functions of Hedgehog signalling across the metazoa. Nature Review Genetics, 12: 393-406.

Jiang J. 2006. Regulation of Hh/Gli signaling by dual ubiquitin pathways. Cell Cycle [Internet], 5: 2457-2463. Accessed: 12 January 2016. Available on: < pubmed/17102630>.

Jin Y, Raviv N, Barnett A, Bambakidis NC, Filichia E, Luo Y. 2015. The shh signaling pathway is upregulated in multiple cell types in cortical ischemia and influences the outcome of stroke in an animal model. PloS One [Internet], 10: e0124657. Accessed: 23 November 2015. Available on: <>.

Katoh Y, Katoh M. 2009. Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Current Molecular Medicine, 9: 873-886.

Khakh BS, Sofroniew MV. 2015. Diversity of astrocyte functions and phenotypes in neural circuits. Nature Neuroscience, 18: 942-952. Kovacs JJ, Whalen EJ, Liu R, Xiao K, Kim J, Chen M, Wang J, Chen W, Lefkowitz RJ. 2008. Beta-arrestin-mediated localization of smoothened to the primary cilium. Science, 320: 1777-1781.

Lowry N, Goderie SK, Lederman P, Charniga C, Gooch MR, Gracey KD, Banerjee A, Punyani S, Silver J, Kane RS, Stern JF, Temple S. 2012. The effect of long-term release of Shh from implanted biodegradable microspheres on recovery from spinal cord injury in mice. Biomaterials, 33: 2892-2901.

Marazziti D, Di Pietro C, Golini E, Mandillo S, La Sala G, Matteoni R, Tocchini-Valentini GP. 2013. Precocious cerebellum development and improved motor functions in mice lacking the astrocyte cilium-, patched 1-associated Gpr37l1 receptor. Proceedings of the National Academy of Sciences of the United States of America, 110: 16486-16491.

Matus DQ, Magie CR, Pang K, Martindale MQ, Thomsen GH. 2008. The Hedgehog gene family of the cnidarian, Nematostella vectensis, and implications for understanding metazoan Hedgehog pathway evolution. Developmental Biology, 313: 501-518.

Miller RH, Szigeti V. 1991. Clonal analysis of astrocyte diversity in neonatal rat spinal cord cultures.Developmental, 113: 353-362. Milligan ED, Watkins LR. 2009. Pathological and protective roles of glia in chronic pain. Nature Reviews Neuroscience, 10: 23-36.

Miyamura T, Morita N, Baba H, Hase S, Kajimoto T, Tsuji, S, Kawata M, Kato I, Mikoshiba K, Ikenaka K. 1998. Metabolic labeling of a subset of glial cells by UDP-galactose: implication for astrocytlineage diversity. Journal of Neuroscience Research, 52: 173-183.

Nagelhus EA, Amiry-Moghaddam M, Bergersen LH, Bjaalie JG,Eriksson J, Gundersen V, Leergaard TB, Morth JP, Storm- Mathisen J, Torp R, Walhovd KB, Tønjum T. 2013. The glia doctrine: addressing the role of glial cells in healthy brain ageing. Mechanisms of Ageing and Development, 134: 449-459.

Nedelcu D, Liu J, Xu Y, Jao C, Salic, A. 2013. Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling. Nature Chemical Biology, 9: 557-564.

Nozawa YI, Lin C, Chuang P-T. 2013. Hedgehog signaling from the primary cilium to the nucleus: an emerging picture of ciliary localization, trafficking and transduction. Current Opinion in Genetics & Development, 23: 429-437.

Okano-Uchida T, Himi T, Komiya Y, Ishizaki Y. 2004. Cerebellar granule cell precursors can differentiate into astroglial cells. Proceedings of the National Academy of Sciences of the United States of America, 101: 1211-1216.

Okuda H, Tatsumi K, Morita-Takemura S, Nakahara K, Nochioka K, Shinjo T, Terada Y, Wanaka A. 2015. Hedgehog Signalin Modulates the Release of Gliotransmitters from Cultured Cerebellar Astrocytes. Neurochemical Research [Internet]: 1-12. Accessed: 21 January 2016. Available on: <>.

Palma V, Lim DA, Dahmane N, Sánchez P, Brionne TC, Herzberg CD, Gitton Y, Carleton A, Alvarez-Buylla A, Ruiz i Altaba A. 2005. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development, 132: 335-344.

Petrova R, Garcia ADR, Joyner AL. 2013. Titration of GLI3 repressor activity by sonic hedgehog signaling is critical for maintaining multiple adult neural stem cell and astrocyte functions. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 33: 17490-17505.

Pitter KL, Tamagno I, Feng X, Ghosal K, Amankulor N, Holland EC, Hambardzumyan D. 2014. The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration-induced lesions. Glia, 62: 1595-1607.

Prat A, Biernacki K, Wosik K, Antel JP. 2001. Glial cell influence on the human blood-brain barrier. Glia, 36: 145-155. Ransom B, Behar T, Nedergaard M. 2003. New roles for astrocytes (stars at last). Trends in Neurosciences, 26: 520-522.

Riobó NA, Lu K, Ai X, Haines GM, Emerson CP. 2006. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proceedings of the National Academy of Sciences of the United States of America, 103: 4505-4510.

Robbins DJ, Fei DL, Riobo NA. 2012. The Hedgehog signal transduction network. Science Signaling [Internet], 5: re6. Accessed: 20 September 2015. Available on: <>.

Robel S, Sontheimer H. 2015. Glia as drivers of abnormal neuronal activity. Nature Neuroscience, 19: 28-33.

Ruiz i Altaba A. 2011. Hedgehog signaling and the Gli code in stem cells, cancer, and metastases. Science Signaling [Internet]: 4, pt9. Accessed: 5 July 2015. Avalaible on: < content/4/200/pt9>.

Ruiz i Altaba A, Palma V, Dahmane N. 2002. Hedgehog-Gli signalling and the growth of the brain. Nature Reviews Neuroscience, 3: 24-33.

Schitine C, Nogaroli L, Costa MR, Hedin-Pereira C. 2015. Astrocyte heterogeneity in the brain: from development to disease. Frontiers in Cellular Neuroscience [Internet], 9: 76. Accessed: 25 November 2015. Available on: <>.

Shi Q, Li S, Li S, Jiang A, Chen Y, Jiang J. 2014. Hedgehog-inducedphosphorylation by CK1 sustains the activity of Ci/Gli activator. Proceedings of the National Academy of Sciences of the United States of America, 111: E5651-E5660.

Sims JR, Lee S-W, Topalkara K, Qiu J, Xu J, Zhou Z, Moskowitz MA. 2009. Sonic hedgehog regulates ischemia/hypoxia-induced neural progenitor proliferation. Stroke; a Journal of Cerebral Circulation, 40: 3618-3626.

Sirko S, Behrendt G, Johansson PA, Tripathi P, Costa M, Bek S, Heinrich C, Tiedt S, Colak D, Dichgans M, Fischer IR, Plesnila N, Staufenbiel M, Haass C, Snapyan M, Saghatelyan A, Tsai LH, Fischer A, Grobe K, Dimou L, Götz M. 2013. Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog. Cell Stem Cell, 12: 426-439.

Ståhlberg A, Andersson D, Aurelius J, Faiz M, Pekna M, Kubista M, Pekny M. 2011. Defining cell populations with single-cell gene expression profiling: correlations and identification of astrocyte subpopulations. Nucleic Acids Research [Internet], 39, e24. Accessed: 20 January 2016. Available on: <http://nar.>.

Stecca B, Ruiz I Altaba A. 2010. Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals. Journal of Molecular Cell Biology, 2: 84-95.

Tabata H. 2015. Diverse subtypes of astrocytes and their development during corticogenesis. Frontiers in Neuroscience, 9: 114.

Tabernero A, Medina JM, Giaume C. 2006. Glucose metabolism and proliferation in glia: role of astrocytic gap junctions. Journal of Neurochemistry, 99: 1049-1061.

Verkhratsky A, Parpura V, Pekna M, Pekny M, Sofroniew M. 2014. Glia in the pathogenesis of neurodegenerative diseases. Biochemichal Society Transactions, 42: 1291-1301.

Rudolf Virchow. 1862. Gesammelte Abhandlungen zur wissenschaftlichen Medizin [Internet]. Sweite unveranderte ausgabe. Accessed: 5 June 2016. Available on: < items/gesammelteabhand00virc/gesammelteabhand00virc.pdf>.

Wallace VA, Raff MC. 1999. A role for Sonic hedgehog in axon-to- astrocyte signalling in the rodent optic nerve. Development,

: 2901-2909.

Wang Y, Jin S, Sonobe Y, Cheng Y, Horiuchi H, Parajuli B, Kawanokuchi J, Mizuno T, Takeuchi H, Suzumura A. 2014. Interleukin-1β induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes. PloS One [Internet], 9: e110024. Accessed: 5 December 2015. Available on: <>.

White R, Krämer-Albers E-M. 2014. Axon-glia interaction and membrane traffic in myelin formation. Frontiers in Cellular Neuroscience, 7: 284.

Xia Y-P, Dai R-L, Li Y-N, Mao L, Xue Y-M, He Q-W, Huang M, Huang Y, Mei Y-W, Hu B. 2012. The protective effect of sonic hedgehog is mediated by the phosphoinositide [corrected] 3-kinase/AKT/Bcl-2 pathway in cultured rat astrocytes under oxidative stress. Neuroscience, 209: 1-11.

Yang C, Rahimpour S, Yu ACH, Lonser RR, Zhuang Z. 2013. Regulation and dysregulation of astrocyte activation and implications in tumor formation. Cellular and molecular life sciences [Internet]: 70, 4201-4211. Accessed: 21 January 2016. Available on: <>.

Yang H, Feng G-D, Olivera C, Jiao X-Y, Vitale A, Gong J, You S-W. 2012. Sonic hedgehog released from scratch-injured astrocytes is a key signal necessary but not sufficient for the astrocyte de- differentiation. Stem Cell Research, 9: 156-166.

Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres

BA. 2012. Genomic analysis of reactive astrogliosis. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 32: 6391-6410.

Zuchero JB and Barres BA. 2015. Glia in mammalian development and disease. Development, 142: 3805-3809.

Cómo citar
Bermúdez-Muñoz O. M. (2017). Señalización Sonic Hedgehog (SHH) en el cerebro adulto: vía crucial para la reactivación de los astrocitos y la reparación del cerebro. Actualidades Biológicas, 38(105), 197-209.
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