Steve Fancy, PhD, DVM

Oligodendrocytes are the myelinating cells of the CNS that enable formation of myelin and saltatory nerve conduction. In Multiple Sclerosis (MS), the most common cause of neurological disability in young adults, myelin sheaths are lost through injury or death of mature oligodendrocytes (OL) as a result of autoimmune damage. White matter disorders are also associated with human newborn neurological injuries leading to Cerebral palsy (CP). CP complicates over 3.3/1000 live births in the United States and the incidence of this devastating condition is on the rise due to the increasing rates of survival of very low birth weight premature infants. In these conditions, myelin sheaths can be regenerated by oligodendrocyte progenitors (OLP) that are recruited to lesions and differentiate in a process called remyelination. But evidence suggests that myelin repair often fails in these diseases and this inhibition of remyelination contributes significantly to ongoing neurological dysfunction, axonal loss and disease progression. In order to understand the regulatory factors relevant in human myelin disorders, it is first critical to understand the cellular mechanisms regulating developmental myelination and the remyelination repair process following injury. My lab is a developmental biology lab, with a disease/injury repair orientation, and access to human developmental brain and MS tissue.

Major Mechanistic and Translational goals:(1) identification of novel factors critical to murine developmental myelination, a questioning of their recapitulation in adult murine remyelination, and validation in human pathological white matter injury tissue (2) gaining a greater understanding of the human white matter lesion as a dysregulated repair environment, and why myelin repair fails in human demyelinating injuries (3) identification and testing of therapeutics to promote repair in human white matter injury.
Education
BA, - , Cambridge University, United Kingdom
MA, - , Cambridge University, United Kingdom
PhD, - , Cambridge University, United Kingdom
VetMB, - , Cambridge University, United Kingdom
Postdoctoral Studies, - Graduate Division, University of California, San Francisco
Websites

  1. Chen J, Crouch EE, Zawadzki ME, Jacobs KA, Mayo LN, Choi JJ, Lin PY, Shaikh S, Tsui J, Gonzalez-Granero S, Waller S, Kelekar A, Kang G, Valenzuela EJ, Birrueta JO, Diafos LN, Wedderburn-Pugh K, Di Marco B, Xia W, Han CZ, Coufal NG, Glass CK, Fancy SPJ, Alfonso J, Kriegstein AR, Oldham MC, Garcia-Verdugo JM, Kutys ML, Lehtinen MK, Combes AJ, Huang EJ. Proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage in prenatal human brain. Nature neuroscience 2024. PMID: 39349662


  2. Mei F, Fancy SPJ, Shen YA, Niu J, Zhao C, Presley B, Miao E, Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L, Franklin RJM, Green A, Hauser SL, Chan JR. Author Correction: Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nature medicine 2024. PMID: 38997609


  3. Leng K, Rooney B, McCarthy F, Xia W, Rose IVL, Bax S, Chin M, Fathi S, Herrington KA, Leonetti M, Kao A, Fancy SPJ, Elias JE, Kampmann M. mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes. Journal of neuroinflammation 2024. PMID: 39118084


  4. Hoi KK, Xia W, Wei MM, Ulloa Navas MJ, Garcia Verdugo JM, Nachury MV, Reiter JF, Fancy SPJ. Primary cilia control oligodendrocyte precursor cell proliferation in white matter injury via Hedgehog-independent CREB signaling. Cell reports 2023. PMID: 37858465


  5. Su Y, Wang X, Yang Y, Chen L, Xia W, Hoi KK, Li H, Wang Q, Yu G, Chen X, Wang S, Wang Y, Xiao L, Verkhratsky A, Fancy SPJ, Yi C, Niu J. Astrocyte endfoot formation controls the termination of oligodendrocyte precursor cell perivascular migration during development. Neuron 2022. PMID: 36384142


  6. Leng K, Rose IVL, Kim H, Xia W, Romero-Fernandez W, Rooney B, Koontz M, Li E, Ao Y, Wang S, Krawczyk M, Tcw J, Goate A, Zhang Y, Ullian EM, Sofroniew MV, Fancy SPJ, Schrag MS, Lippmann ES, Kampmann M. CRISPRi screens in human iPSC-derived astrocytes elucidate regulators of distinct inflammatory reactive states. Nature neuroscience 2022. PMID: 36303069


  7. Xia W, Fancy SPJ. Mechanisms of oligodendrocyte progenitor developmental migration. Developmental neurobiology 2021. PMID: 34643996


  8. Niu J, Yu G, Wang X, Xia W, Wang Y, Hoi KK, Mei F, Xiao L, Chan JR, Fancy SPJ. Oligodendroglial ring finger protein Rnf43 is an essential injury-specific regulator of oligodendrocyte maturation. Neuron 2021. PMID: 34390652


  9. Dorrier CE, Aran D, Haenelt EA, Sheehy RN, Hoi KK, Pintaric L, Chen Y, Lizama CO, Cautivo KM, Weiner GA, Popko B, Fancy SPJ, Arnold TD, Daneman R. CNS fibroblasts form a fibrotic scar in response to immune cell infiltration. Nature neuroscience 2021. PMID: 33526922


  10. Niu J, Tsai HH, Hoi KK, Huang N, Yu G, Kim K, Baranzini SE, Xiao L, Chan JR, Fancy SPJ. Aberrant oligodendroglial-vascular interactions disrupt the blood-brain barrier, triggering CNS inflammation. Nature neuroscience 2019. PMID: 30988524


  11. Baror R, Neumann B, Segel M, Chalut KJ, Fancy SPJ, Schafer DP, Franklin RJM. Transforming growth factor-beta renders ageing microglia inhibitory to oligodendrocyte generation by CNS progenitors. Glia 2019. PMID: 30861188


  12. Daynac M, Chouchane M, Collins HY, Murphy NE, Andor N, Niu J, Fancy SPJ, Stallcup WB, Petritsch CK. Lgl1 controls NG2 endocytic pathway to regulate oligodendrocyte differentiation and asymmetric cell division and gliomagenesis. Nature communications 2018. PMID: 30131568


  13. Wang F, Yang YJ, Yang N, Chen XJ, Huang NX, Zhang J, Wu Y, Liu Z, Gao X, Li T, Pan GQ, Liu SB, Li HL, Fancy SPJ, Xiao L, Chan JR, Mei F. Enhancing Oligodendrocyte Myelination Rescues Synaptic Loss and Improves Functional Recovery after Chronic Hypoxia. Neuron 2018. PMID: 30078577


  14. Cree BAC, Niu J, Hoi KK, Zhao C, Caganap SD, Henry RG, Dao DQ, Zollinger DR, Mei F, Shen YA, Franklin RJM, Ullian EM, Xiao L, Chan JR, Fancy SPJ. Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Brain : a journal of neurology 2018. PMID: 29244098


  15. Petersen MA, Ryu JK, Chang KJ, Etxeberria A, Bardehle S, Mendiola AS, Kamau-Devers W, Fancy SPJ, Thor A, Bushong EA, Baeza-Raja B, Syme CA, Wu MD, Rios Coronado PE, Meyer-Franke A, Yahn S, Pous L, Lee JK, Schachtrup C, Lassmann H, Huang EJ, Han MH, Absinta M, Reich DS, Ellisman MH, Rowitch DH, Chan JR, Akassoglou K. Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage. Neuron 2017. PMID: 29103804


  16. Dawes WJ, Zhang X, Fancy SPJ, Rowitch D, Marino S. Moderate-Grade Germinal Matrix Haemorrhage Activates Cell Division in the Neonatal Mouse Subventricular Zone. Developmental neuroscience 2017. PMID: 28343214


  17. Mei F, Lehmann-Horn K, Shen YA, Rankin KA, Stebbins KJ, Lorrain DS, Pekarek K, A Sagan S, Xiao L, Teuscher C, von Büdingen HC, Wess J, Lawrence JJ, Green AJ, Fancy SP, Zamvil SS, Chan JR. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. eLife 2016. PMID: 27671734


  18. Tsai HH, Niu J, Munji R, Davalos D, Chang J, Zhang H, Tien AC, Kuo CJ, Chan JR, Daneman R, Fancy SP. Oligodendrocyte precursors migrate along vasculature in the developing nervous system. Science (New York, N.Y.) 2016. PMID: 26798014


  19. Zhao C, Ma D, Zawadzka M, Fancy SP, Elis-Williams L, Bouvier G, Stockley JH, de Castro GM, Wang B, Jacobs S, Casaccia P, Franklin RJ. Sox2 Sustains Recruitment of Oligodendrocyte Progenitor Cells following CNS Demyelination and Primes Them for Differentiation during Remyelination. The Journal of neuroscience : the official journal of the Society for Neuroscience 2015. PMID: 26290228


  20. Lee HK, Laug D, Zhu W, Patel JM, Ung K, Arenkiel BR, Fancy SP, Mohila C, Deneen B. Apcdd1 stimulates oligodendrocyte differentiation after white matter injury. Glia 2015. PMID: 25946682


  21. Lee HK, Chaboub LS, Zhu W, Zollinger D, Rasband MN, Fancy SP, Deneen B. Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS. Neuron 2015. PMID: 25754822


  22. Yuen TJ, Silbereis JC, Griveau A, Chang SM, Daneman R, Fancy SPJ, Zahed H, Maltepe E, Rowitch DH. Oligodendrocyte-encoded HIF function couples postnatal myelination and white matter angiogenesis. Cell 2014. PMID: 25018103


  23. Mei F, Fancy SPJ, Shen YA, Niu J, Zhao C, Presley B, Miao E, Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L, Franklin RJM, Green A, Hauser SL, Chan JR. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nature medicine 2014. PMID: 24997607


  24. Fancy SP, Harrington EP, Baranzini SE, Silbereis JC, Shiow LR, Yuen TJ, Huang EJ, Lomvardas S, Rowitch DH. Parallel states of pathological Wnt signaling in neonatal brain injury and colon cancer. Nature neuroscience 2014. PMID: 24609463


  25. Molofsky AV, Glasgow SM, Chaboub LS, Tsai HH, Murnen AT, Kelley KW, Fancy SP, Yuen TJ, Madireddy L, Baranzini S, Deneen B, Rowitch DH, Oldham MC. Expression profiling of Aldh1l1-precursors in the developing spinal cord reveals glial lineage-specific genes and direct Sox9-Nfe2l1 interactions. Glia 2013. PMID: 23840004


  26. Fancy SP, Glasgow SM, Finley M, Rowitch DH, Deneen B. Evidence that nuclear factor IA inhibits repair after white matter injury. Annals of neurology 2012. PMID: 22807310


  27. Tsai HH, Li H, Fuentealba LC, Molofsky AV, Taveira-Marques R, Zhuang H, Tenney A, Murnen AT, Fancy SP, Merkle F, Kessaris N, Alvarez-Buylla A, Richardson WD, Rowitch DH. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science (New York, N.Y.) 2012. PMID: 22745251


  28. Chong SY, Rosenberg SS, Fancy SP, Zhao C, Shen YA, Hahn AT, McGee AW, Xu X, Zheng B, Zhang LI, Rowitch DH, Franklin RJ, Lu QR, Chan JR. Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination. Proceedings of the National Academy of Sciences of the United States of America 2011. PMID: 22160722


  29. Huang JK, Fancy SP, Zhao C, Rowitch DH, Ffrench-Constant C, Franklin RJ. Myelin regeneration in multiple sclerosis: targeting endogenous stem cells. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 2011. PMID: 21904791


  30. Fancy SP, Harrington EP, Yuen TJ, Silbereis JC, Zhao C, Baranzini SE, Bruce CC, Otero JJ, Huang EJ, Nusse R, Franklin RJ, Rowitch DH. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nature neuroscience 2011. PMID: 21706018


  31. Fancy SP, Chan JR, Baranzini SE, Franklin RJ, Rowitch DH. Myelin regeneration: a recapitulation of development? Annual review of neuroscience 2011. PMID: 21692657


  32. Harrington EP, Zhao C, Fancy SP, Kaing S, Franklin RJ, Rowitch DH. Oligodendrocyte PTEN is required for myelin and axonal integrity, not remyelination. Annals of neurology 2010. PMID: 20853437


  33. Zawadzka M, Rivers LE, Fancy SP, Zhao C, Tripathi R, Jamen F, Young K, Goncharevich A, Pohl H, Rizzi M, Rowitch DH, Kessaris N, Suter U, Richardson WD, Franklin RJ. CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell stem cell 2010. PMID: 20569695


  34. Fancy SP, Kotter MR, Harrington EP, Huang JK, Zhao C, Rowitch DH, Franklin RJ. Overcoming remyelination failure in multiple sclerosis and other myelin disorders. Experimental neurology 2010. PMID: 20044992


  35. Zhao C, Fancy SP, Franklin RJ, ffrench-Constant C. Up-regulation of oligodendrocyte precursor cell alphaV integrin and its extracellular ligands during central nervous system remyelination. Journal of neuroscience research 2009. PMID: 19739252


  36. Fancy SP, Baranzini SE, Zhao C, Yuk DI, Irvine KA, Kaing S, Sanai N, Franklin RJ, Rowitch DH. Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes & development 2009. PMID: 19515974


  37. Bennett RC, Fancy SP, Walsh CM, Brown AJ, Taylor PM. Comparison of sevoflurane and isoflurane in dogs anaesthetised for clinical surgical or diagnostic procedures. The Journal of small animal practice 2008. PMID: 18631219


  38. Zhao C, Fancy SP, ffrench-Constant C, Franklin RJ. Osteopontin is extensively expressed by macrophages following CNS demyelination but has a redundant role in remyelination. Neurobiology of disease 2008. PMID: 18539470


  39. Ligon KL, Fancy SP, Franklin RJ, Rowitch DH. Olig gene function in CNS development and disease. Glia 2006. PMID: 16652341


  40. Zhao C, Fancy SP, Magy L, Urwin JE, Franklin RJ. Stem cells, progenitors and myelin repair. Journal of anatomy 2005. PMID: 16185249


  41. Zhao C, Fancy SP, Kotter MR, Li WW, Franklin RJ. Mechanisms of CNS remyelination--the key to therapeutic advances. Journal of the neurological sciences 2005. PMID: 15949498


  42. Arnett HA, Fancy SP, Alberta JA, Zhao C, Plant SR, Kaing S, Raine CS, Rowitch DH, Franklin RJ, Stiles CD. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science (New York, N.Y.) 2004. PMID: 15604411


  43. Fancy SP, Zhao C, Franklin RJ. Increased expression of Nkx2.2 and Olig2 identifies reactive oligodendrocyte progenitor cells responding to demyelination in the adult CNS. Molecular and cellular neurosciences 2004. PMID: 15519240