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Special thanks to Prof. Jeremy Lee of UCSC, who taught me pretty much everything I know about the molecular mechanisms of development.
Sonic hedgehog - the protein
Sonic hedgehog - the protein
Cliff Tabin's lab is credited with the discovery of the protein in humans.
SHH sonic hedgehog signaling molecule [Homo sapiens (human)] - Gene - NCBI. (n.d.). https://www.ncbi.nlm.nih.gov/gene/6469
Bürglin, T. R. (2008). The Hedgehog protein family. GenomeBiology.com (London. Print), 9(11), 241. https://doi.org/10.1186/gb-2008-9-11-241
Basic Development Concepts
Basic Development Concepts
I used this site for the image on the left, as well as many of the other embryonic slices included in my presentation.
Thowfeequ, S., & Srinivas, S. (2022). Embryonic and extraembryonic tissues during mammalian development: shifting boundaries in time and space. Philosophical Transactions of the Royal Society B, 377(1865). https://doi.org/10.1098/rstb.2021.0255
Chapter 18. Week 3 of Development: Trilaminar Germ Disk Embryo Formation and Gastrulation - Review of Medical Embryology Book - LifeMap Discovery. (n.d.). https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-18-week-3-of-development-trilaminar-germ-disk-embryo-formation-and-gastrulation
⬅️Changes in morphology of the human brain throughout development.
Stiles, J., & Jernigan, T. L. (2010). The Basics of Brain Development. Neuropsychology Review, 20(4), 327–348. https://doi.org/10.1007/s11065-010-9148-4
Alberts, B. (2002). Neural development. Molecular Biology of the Cell - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK26814/
Gilbert, S. F. (2000). Differentiation of the neural tube. Developmental Biology - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK10034/
Hedgehog Signaling Pathway
Hedgehog Signaling Pathway
Wilson, C. W., & Chuang, P. (2010). Mechanism and evolution of cytosolic Hedgehog signal transduction. Development, 137(13), 2079–2094. https://doi.org/10.1242/dev.045021
⬅️SHH pathway.
Choudhry, Z., Rikani, A. A., Choudhry, A. M., Tariq, S., Zakaria, F., Asghar, M. W., Sarfraz, M., Haider, K., Shafiq, A. A., & Mobassarah, N. J. (2014). Sonic hedgehog signalling pathway: a complex network. Annals of Neurosciences, 21(1). https://doi.org/10.5214/ans.0972.7531.210109
Lee, R. T. H., Zhao, Z., & Ingham, P. W. (2016). Hedgehog signalling. Development, 143(3), 367–372. https://doi.org/10.1242/dev.120154
Hedgehog signaling pathway: an overview | Abcam. (2023, August 16). https://www.abcam.com/pathways/hedgehog-signaling-pathway
⬅️ Non-canonical pathway.
Carballo, G. B., Honorato, J., De Lopes, G. P. F., & De Sampaio E Spohr, T. C. L. (2018). A highlight on Sonic hedgehog pathway. Cell Communication and Signaling, 16(1). https://doi.org/10.1186/s12964-018-0220-7
Hedgehog Signaling | Cell Signaling Technology. (n.d.). Cell Signaling Technology. https://www.cellsignal.com/pathways/hedgehog-signaling-pathway
Members of the Hedgehog Signaling Pathway
Sufu
Sufu
An important regulator in the signaling pathway
⬅️This demonstrates the suppressive functions of Sufu in SHH signaling.
Huang, D., Wang, Y., Tang, J., & Luo, S. (2018). Molecular mechanisms of suppressor of fused in regulating the hedgehog signalling pathway (Review). Oncology Letters. https://doi.org/10.3892/ol.2018.8142
Han, Y., Shi, Q., & Jen, J. (2015). Multisite interaction with Sufu regulates Ci/Gli activity through distinct mechanisms in Hh signal transduction. Proceedings of the National Academy of Sciences of the United States of America, 112(20), 6383–6388. https://doi.org/10.1073/pnas.1421628112
Suppressor of fused. (n.d.). https://www.sdbonline.org/sites/fly/segment/sufused1.htm
Patched and Smoothened
Patched and Smoothened
SHH's receptor, patched, inhibits smoothened until SHH binds.
⬅️The inactive and active states of smoothened. Activation requires cholesterol binding.
Huang, P., Zheng, S., Wierbowski, B. M., Kim, Y. C., Nedelcu, D., Aravena, L., Liu, J., Kruse, A. C., & Salic, A. (2018). Structural basis of smoothened activation in hedgehog signaling. Cell, 174(2), 312-324.e16. https://doi.org/10.1016/j.cell.2018.04.029
Petrov, K., De Almeida Magalhães, T., & Salic, A. (2021). Mechanism and ultrasensitivity in Hedgehog signaling revealed by Patched1 disease mutations. Proceedings of the National Academy of Sciences of the United States of America, 118(6). https://doi.org/10.1073/pnas.2006800118
Kif7
Kif7
A cilia-associated protein that transmits the SHH signal after reacting with smoothened.
⬅️ A mutated Kif7 protein (maki) causes dorsal expansion of the motor neuron progenitor domain compared to the wild type (wt).
Liem, K. F., He, M., Ocbina, P. J. R., & Anderson, K. V. (2009). Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proceedings of the National Academy of Sciences of the United States of America, 106(32), 13377–13382. https://doi.org/10.1073/pnas.0906944106
Gli Transcription Factors
Gli Transcription Factors
These transcription factors are generally activated by SHH, and the SHH gradient is mirrored in the Gli gradient.
⬅️The on/off states correlate to Gli activators and Gli repressors, respectively.
Sigafoos, A. N., Paradise, B. D., & Fernandez-Zapico, M. E. (2021). Hedgehog/GLI Signaling Pathway: Transduction, regulation, and implications for disease. Cancers, 13(14), 3410. https://doi.org/10.3390/cancers13143410
Stamataki, D., Ulloa, F., Tsoni, S. V., Mynett, A., & Briscoe, J. (2005). A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube. Genes & Development, 19(5), 626–641. https://doi.org/10.1101/gad.325905
Diao, Y., Rahman, M. F., Vyatkin, Y., Azatyan, A., St Laurent, G., Kapranov, P., & Zaphiropoulos, P. G. (2018). Identification of novel GLI1 target genes and regulatory circuits in human cancer cells. Molecular Oncology, 12(10), 1718–1734. https://doi.org/10.1002/1878-0261.12366
Homeobox Genes
Homeobox Genes
(From same study as above image). Expression of specific homeobox genes across the ventral domains in the developing neural tube.
Progenitor domains that result from different expression levels of homeobox genes/proteins.
Respective fates of each progenitor domain based on the type and amount of homeobox genes expressed.
These genes encode proteins involved in body planning.
⬅️ Some homeobox proteins being expressed across the SHH gradient
Dessaud, E., McMahon, A. P., & Briscoe, J. (2008). Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network. Development, 135(15), 2489–2503. https://doi.org/10.1242/dev.009324
Briscoe, J., Pierani, A., M Jessell, T., & Ericson, J. (2000). A Homeodomain Protein Code Specifies Progenitor Cell Identity and Neuronal Fate in the Ventral Neural Tube. Cell, 101(4), 435–445. https://doi.org/10.1016/S0092-8674(00)80853-3
Class I Proteins
Class I Proteins
Transcription of the genes that encode these proteins are decreased by SHH.
Pachikara, A., Dolson, D. K., Martinu, L., Riccomagno, M. M., Jeong, Y., & Epstein, D. J. (2007). Activation of Class I transcription factors by low level Sonic hedgehog signaling is mediated by Gli2-dependent and independent mechanisms. Developmental Biology, 305(1), 52–62. https://doi.org/10.1016/j.ydbio.2007.01.035
Murdoch, B., DelConte, C., & García-Castro, M. I. (2012). PAx7 lineage contributions to the mammalian neural crest. PLOS ONE, 7(7), e41089. https://doi.org/10.1371/journal.pone.0041089
Lin, J., Wang, C., Yang, C., Fu, S., & Redies, C. (2015). Pax3 and Pax7 interact reciprocally and regulate the expression of cadherin-7 through inducing neuron differentiation in the developing chicken spinal cord. Journal of Comparative Neurology, 524(5), 940–962. https://doi.org/10.1002/cne.23885
Nishina, S., Kohsaka, S., Yamaguchi, Y., Handa, H., Kawakami, K., Fujisawa, H., & Azuma, N. (1999). PAX6 expression in the developing human eye. British Journal of Ophthalmology, 83(6), 723–727. https://doi.org/10.1136/bjo.83.6.723
Sartoretti, M. M., Campetella, C. A., & Lanuza, G. M. (2022). Dbx1 controls the development of astrocytes of the intermediate spinal cord by modulating Notch signaling. Development, 149(15). https://doi.org/10.1242/dev.200750
Class II Proteins
Class II Proteins
Transcription of the genes that encode these proteins are increased by SHH.
Mansour, A. A., Khazanov-Zisman, S., Netser, Y., Klar, A., & Ben-Arie, N. (2014). Nato3 plays an integral role in dorsoventral patterning of the spinal cord by segregating floor plate/p3 fates via Nkx2.2 suppression and Foxa2 maintenance. Development, 141(3), 574–584. https://doi.org/10.1242/dev.104372
Zhang, C., Huang, H., Chen, Z., Zhang, Z., Lu, W., & Qiu, M. (2020). The transcription factor NKX2-2 regulates oligodendrocyte differentiation through domain-specific interactions with transcriptional corepressors. Developmental Biology, 295(7), 1879–1888. https://doi.org/10.1074/jbc.RA119.011163
Li, H., De Faria, J. P., Andrew, P., Nitarska, J., & Richardson, W. D. (2011). Phosphorylation regulates OLIG2 cofactor choice and the motor Neuron-Oligodendrocyte fate switch. Neuron, 69(5), 918–929. https://doi.org/10.1016/j.neuron.2011.01.030
Sander, M., Paydar, S., Ericson, J., Briscoe, J., Berber, E., German, M. S., Jessell, T. M., & Rubenstein, J. L. (2000). Ventral neural patterning by Nkx homeobox genes: Nkx6.1 controls somatic motor neuron and ventral interneuron fates. Genes & Development, 14(17), 2134–2139. https://doi.org/10.1101/gad.820400
Specific Roles of the SHH Pathway
Specific Roles of the SHH Pathway
Neural Development
⬅️ Areas in which SHH is expressed along the neural tube in the human embryo.
Douceau, S., Guerrero, T. D., & Ferent, J. (2023). Establishing Hedgehog Gradients during Neural Development. Cells, 12(2), 225. https://doi.org/10.3390/cells12020225
Ribes, V., Balaskas, N., Sasai, N., Cruz, C., Dessaud, E., Mas, J., Tozer, S., Yang, L., Novitch, B. G., Martí, E., & Briscoe, J. (2010). Distinct Sonic Hedgehog signaling dynamics specify floor plate and ventral neuronal progenitors in the vertebrate neural tube. Genes & Development, 24(11), 1186–1200. https://doi.org/10.1101/gad.559910
⬅️ Specification of different progenitor areas by SHH in the neural tube over time.
Danesin, C., & Soula, C. (2017). Moving the Shh Source over Time: What Impact on Neural Cell Diversification in the Developing Spinal Cord? Journal of Developmental Biology, 5(2), 4. https://doi.org/10.3390/jdb5020004
Kahane, N., & Kalcheim, C. (2020). Neural tube development depends on notochord-derived Sonic hedgehog released into the sclerotome. Development. https://doi.org/10.1242/dev.183996
Yang, C., Yan, Q., & Sun, Z. (2021). The role of sonic hedgehog pathway in the development of the central nervous system and Aging-Related Neurodegenerative Diseases. Frontiers in Molecular Biosciences, 8. https://doi.org/10.3389/fmolb.2021.711710
⬅️ Gli activator and Gli repressor activity along the ventral neural tube, influenced by the SHH gradient, and the specification of the progenitor areas.
Jacob, J. R., & Briscoe, J. (2003). Gli proteins and the control of spinal‐cord patterning. EMBO Reports, 4(8), 761–765. https://doi.org/10.1038/sj.embor.embor896
Ravanelli, A. M., & Appel, B. (2015). Motor neurons and oligodendrocytes arise from distinct cell lineages by progenitor recruitment. Genes & Development, 29(23), 2504–2515. https://doi.org/10.1101/gad.271312.115
Ericson, J., Morton, S., Kawakami, A., Roelink, H., & Jessell, T. M. (1996). Two Critical Periods of Sonic Hedgehog Signaling Required for the Specification of Motor Neuron Identity. Cell, 87(4), 661–673. https://doi.org/10.1016/s0092-8674(00)81386-0
Traiffort, E., Zakaria, M., Laouarem, Y., & Ferent, J. (2016). Hedgehog: A Key Signaling in the Development of the Oligodendrocyte Lineage. Journal of Developmental Biology, 4(3), 28. https://doi.org/10.3390/jdb4030028
⬅️ Two different SHH signaling pathways and their associations with differing developmental functions in the human nervous system.
Belgacem, Y. H., Hamilton, A. M., Shim, S., Spencer, K., & Borodinsky, L. N. (2016). The Many Hats of Sonic Hedgehog Signaling in Nervous System Development and Disease. Journal of Developmental Biology, 4(4), 35. https://doi.org/10.3390/jdb4040035
Development of Specific Structures via the Neural Tube
Areas of the developing brain. SHH mainly acts in the prosencephalon and its subdivisions.
Eye Development
Eye Development
Kozmik, Z., Daube, M., Frei, E., Norman, B., Kos, L., Dishaw, L. J., Noll, M., & Piatigorsky, J. (2003). Role of Pax Genes in Eye Evolution. Developmental Cell, 5(5), 773–785. https://doi.org/10.1016/s1534-5807(03)00325-3
Bosze, B., Suarez-Navarro, J., Soofi, A., Lauderdale, J. D., Dressler, G. R., & Brown, N. L. (2021). Multiple roles for Pax2 in the embryonic mouse eye. Developmental Biology, 472, 18–29. https://doi.org/10.1016/j.ydbio.2020.12.020
Hanson, I. (2003). PAX6 and congenital eye malformations. Pediatric Research, 54(6), 791–796. https://doi.org/10.1203/01.pdr.0000096455.00657.98
Embryology of the Eye and Ocular Adnexa - EyeWiki. (2021, November 29). https://eyewiki.aao.org/Embryology_of_the_Eye_and_Ocular_Adnexa#Early_Embryologic_Development
Adler, R., & Canto-Soler, M. V. (2007). Molecular mechanisms of optic vesicle development: Complexities, ambiguities and controversies. Developmental Biology, 305(1), 1–13. https://doi.org/10.1016/j.ydbio.2007.01.045
Brain Development
Brain Development
⬅️ Mutations in genes that promote SHH (denoted by 🔼) lead to abnormalities in the forebrain and, therefore, in the face.
Sagai, T., Amano, T., Maeno, A., Ajima, R., & Shiroishi, T. (2019). SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization. Proceedings of the National Academy of Sciences of the United States of America, 116(47), 23636–23642. https://doi.org/10.1073/pnas.1901732116
Memi, F., Zecevic, N., & Radonjić, N. V. (2018). Multiple roles of Sonic Hedgehog in the developing human cortex are suggested by its widespread distribution. Brain Structure & Function, 223(5), 2361–2375. https://doi.org/10.1007/s00429-018-1621-5
Himmelstein, D. S., Bi, C., Clark, B. S., Bai, B., & Kohtz, J. D. (2010). Balanced Shh signaling is required for proper formation and maintenance of dorsal telencephalic midline structures. BMC Developmental Biology, 10(1). https://doi.org/10.1186/1471-213x-10-118
Araújo, G. L. L., Araújo, J. a. M., Schroeder, T., Tort, A. B. L., & Costa, M. R. (2014). Sonic hedgehog signaling regulates mode of cell division of early cerebral cortex progenitors and increases astrogliogenesis. Frontiers in Cellular Neuroscience, 8. https://doi.org/10.3389/fncel.2014.00077
⬅️ Overactivation of SHH disrupts the development of distinct cell groups in the cerebellum, and leads to the formation of medulloblastoma.
Wang, W., Shiraishi, R., & Kawauchi, D. (2022). Sonic Hedgehog Signaling in Cerebellar Development and Cancer. Frontiers in Cell and Developmental Biology, 10. https://doi.org/10.3389/fcell.2022.864035
⬅️ Altering the amount and location of SHH expression can lead to facial abnormalities. 48 hours after implantation with SHH beads, chick embryos showed facial changes, such as small nasal pits and an absent frontonasal process.
Hu, D., & Marcucio, R. (2008). A SHH-responsive signaling center in the forebrain regulates craniofacial morphogenesis via the facial ectoderm. Development, 136(1), 107–116. https://doi.org/10.1242/dev.026583
Axon Guidance
Axon Guidance
A Role for Sonic Hedgehog in Axon Guidance. (n.d.). www.rndsystems.com. https://www.rndsystems.com/resources/articles/role-sonic-hedgehog-axon-guidance
Sonic Hedgehog: a morphogen involved in axon guidance. (n.d.). www.rndsystems.com. https://www.rndsystems.com/resources/articles/sonic-hedgehog-morphogen-involved-axon-guidance
Avilés, E. C., Wilson, N. H., & Stoeckli, E. T. (2012). Sonic hedgehog and Wnt: antagonists in morphogenesis but collaborators in axon guidance. Frontiers in Cellular Neuroscience, 7. https://doi.org/10.3389/fncel.2013.00086
Limb Development
⬅️ Wing development in a chick embryo. A-C show normal wing development with an SHH gradient. D-F show implementation of an SHH graft that creates extra, mirror-imaged digits.
Tickle, C., & Towers, M. (2017). Sonic Hedgehog Signaling in Limb Development. Frontiers in Cell and Developmental Biology, 5. https://doi.org/10.3389/fcell.2017.00014
Rodrigues, A. R., Yakushiji-Kaminatsui, N., Atsuta, Y., Andrey, G., Schorderet, P., Duboule, D., & Tabin, C. J. (2017). Integration of Shh and Fgf signaling in controlling Hox gene expression in cultured limb cells. Proceedings of the National Academy of Sciences of the United States of America, 114(12), 3139–3144. https://doi.org/10.1073/pnas.1620767114
Pathology
Pathology
Murdoch, J., & Copp, A. J. (2010). The relationship between sonic Hedgehog signaling, cilia, and neural tube defects. Birth Defects Research, 88(8), 633–652. https://doi.org/10.1002/bdra.20686
Holoprosencephaly
Holoprosencephaly
⬅️ The different signaling molecules involved in the craniofacial development of mammals.
Petryk, A., Graf, D., & Marcucio, R. (2014). Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans. Wiley Interdisciplinary Reviews-Developmental Biology, 4(1), 17–32. https://doi.org/10.1002/wdev.161
Loo, C., Pearen, M. A., & Ramm, G. A. (2021). The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes. International Journal of Molecular Sciences, 22(18), 9854. https://doi.org/10.3390/ijms22189854
⬅️ A-C shows a normal brain with complete hemisphere divisions. D-F shows a brain with no hemisphere divisions, resulting in a single lobe. (Hence "alobar holoprosencephaly."
Geng, X., & Oliver, G. (2009). Pathogenesis of holoprosencephaly. Journal of Clinical Investigation, 119(6), 1403–1413. https://doi.org/10.1172/jci38937
Holoprosencephaly (HPE) Life Expectancy, Symptoms & Causes. (2021, November 5). eMedicineHealth. https://www.emedicinehealth.com/how_long_can_babies_live_with_holoprosencephaly/article_em.htm
Ramakrishnan, S. (2022, July 18). Holoprosencephaly. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK560861/
Odent, S., Attié-Bitach, T., Blayau, M., Mathieu, M., Auge, J., Delezoide, A., Gall, J. Y. L., Marec, B. L., Munnich, A., David, V., & Vekemans, M. (1999). Expression of the Sonic hedgehog (SHH) Gene during Early Human Development and Phenotypic Expression of New Mutations Causing Holoprosencephaly. Human Molecular Genetics, 8(9), 1683–1689. https://doi.org/10.1093/hmg/8.9.1683
Eye Malformations
Cyclopia - EyeWiki. (2023, January 24). https://eyewiki.aao.org/Cyclopia#Pathophysiology
Cavodeassi, F., Creuzet, S., & Etchevers, H. C. (2018). The hedgehog pathway and ocular developmental anomalies. Human Genetics, 138(8–9), 917–936. https://doi.org/10.1007/s00439-018-1918-8
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