Steve Fancy, PhD, DVM

Assistant Professor
Department of Pediatrics
FancyS@stemcell.ucsf.edu

Background:
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.

On-going Research:

Wnt pathway as a potent inhibitor of oligodendrocyte differentiation: It is becoming increasingly accepted that myelin repair fails in MS and newborn brain injury due to a failure of oligodendrocyte differentiation, and that OLP are recruited to lesions but are unable to differentiate into mature myelin forming OL. In previous work, I have shown that the Wnt pathway is a critical inhibitory pathway for oligodendrocyte differentiation, controlling the timing of this process, and if dysregulated can lead to failed developmental myelination and remyelination. But it has been unclear how the pathway mediates these differentiation-inhibitory effects. Ongoing work using ChIP-seq will identify downstream targets of the Wnt pathway in oligodendrocyte lineage which may mediate these effects. Preliminary evidence for instance suggests that the Wnt target transcription factor SP5 is a novel key regulator of OL biology, binding to multiple mature myelin gene promoters and acting in a balance with family member SP1 in determining OL differentiation

Parallel states of Pathological Wnt Signaling in colon cancer and non-genetic neonatal brain injury: Whilst the Wnt pathway is expressed in OL lineage in human white matter injury and may contribute to failed repair, it has not been clear whether the pathway is pathologically dysregulated in the setting of human injury.  In current unpublished work, I have demonstrated that different threshold states of Wnt signaling can exist in the OL lineage, akin to the different states that can exist in colon epithelium (where low threshold Wnt signaling mediates normal colon epithelium turnover and transition to a high threshold state leads to pathology and adenocarcinoma). Surprisingly, oligodendrocyte progenitors (OLPs) in lesions of human neonatal white matter brain injury and multiple sclerosis express multiple genes characteristic of colon cancer, suggesting that parallel states of pathological high threshold Wnt exist in human white matter injury and colon cancer. It seems that it may be defective Wnt repressor tone which mediates this transition to a pathological Wnt state in OLPs, and ongoing work using new transgenics will evaluate the function of several critical Wnt pathway repressors in developmental myelination and remyelination.

Promoting Remyelination in optic neuritis: Current work has identified the small molecule drug XAV939 as an enhancer of remyelination when injected focally into mouse remyelinating lesions, via its Axin2 stabilization and Wnt inhibitory effects. In MS, demyelination in the optic nerve occurs in 70% of patients, and this optic neuritis leads to significant degradation of vision specific quality-of-life. We propose the local delivery of XAV939 into mouse EAE optic neuritis either via focal injection or via sustained release from implanted polycaprolactone drug delivery films. This has the potential to promote optic nerve remyelination and axonal survival, serving as proof of principle for a therapy in human optic neuritis.

Primary Thematic Area: 
Developmental & Stem Cell Biology
Secondary Thematic Area: 
Neurobiology
Research Summary: 
Molecular regulation of oligodendrocyte myelination during brain development and remyelination following injury

Websites

Featured Publications: 

Oligodendrocyte precursors migrate along vasculature in the developing nervous system.

Science (New York, N.Y.)

Tsai HH, Niu J, Munji R, Davalos D, Chang J, Zhang H, Tien AC, Kuo CJ, Chan JR, Daneman R, Fancy SP

Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis.

Nature medicine

Mei F, Fancy SP, Shen YA, Niu J, Zhao C, Presley B, Miao E, Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L, Franklin RJ, Green A, Hauser SL, Chan JR

Parallel states of pathological Wnt signaling in neonatal brain injury and colon cancer.

Nature neuroscience

Fancy SP, Harrington EP, Baranzini SE, Silbereis JC, Shiow LR, Yuen TJ, Huang EJ, Lomvardas S, Rowitch DH

Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination.

Nature neuroscience

Fancy SP, Harrington EP, Yuen TJ, Silbereis JC, Zhao C, Baranzini SE, Bruce CC, Otero JJ, Huang EJ, Nusse R, Franklin RJ, Rowitch DH

Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS.

Genes & development

Fancy SP, Baranzini SE, Zhao C, Yuk DI, Irvine KA, Kaing S, Sanai N, Franklin RJ, Rowitch DH

bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS.

Science (New York, N.Y.)

Arnett HA, Fancy SP, Alberta JA, Zhao C, Plant SR, Kaing S, Raine CS, Rowitch DH, Franklin RJ, Stiles CD