School of Veterinary Medicine, Room 3354C
2015 Linden Drive
Madison, WI, 53706
MBBS, Grant Medical College, Mumbai, India
PhD, Northwestern University, Chicago, USA
Regulation of Neural Stem Cells in Disorders of Myelination
Our lab focuses on how neural stem cells generate myelin in the brain during development as well as during recovery from a demyelinating insult or remyelination. Our primary goal is to understand the disease process and identify factors that can help repair the brain in disorders of myelin, including Down Syndrome (DS), Pelizaeus Merzbacher Disease (PMD) and Multiple Sclerosis (MS). These diseases cause significant morbidity in humans; however their pathogenesis and repair mechanisms are unknown.
The myelin sheath is a specialized membrane that wraps around the nerves in the brain. In demyelinating diseases, myelin is disrupted resulting in severe neurological defects due to conduction block ultimately leading to the loss of axons. The goal in inherited myelin diseases like PMD and DS is to myelinate axons that have not been ensheathed; while in MS, the goal is to ensheath the axons that have lost their myelin i.e. demyelinated axons. Myelin is synthesized by oligodendrocytes that can simultaneously enwrap many axons. After a demyelination event, new oligodendrocytes are generated by stem cells in the brain but this process remains incomplete resulting in partial repair.
The stem cells in the brain require a growth factor, Sonic Hedgehog (Shh) for their survival in adult brain and also for generating oligodendrocytes during development. However, the role of Shh in generating oligodendrocytes from stem cells in embryos and adults is not fully characterized. Our goal is to further understand the molecular underpinnings of Shh and other pathways in myelination and remyelination by stem cells in the normal and diseased mouse brains. We use mouse models of myelin diseases and genetically remove components of each pathway in the neural stem cells to study their effect on remyelination. These studies will provide new insights into the role of the signaling pathways in regulating activation and recruitment of stem cells in myelin disorders. Understanding the origin of remyelinating cells and the signals which trigger their activation, migration and differentiation has major therapeutic implications for myelin disorders.
Samanta J, Grund EM, Silva HM, Lafaille JJ, Fishell G and Salzer JL (2015). Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. Nature, 526: 448-452
Samanta J*, Alden T*, Gobeske K, Kan L and Kessler JA (2010). Noggin protects against ischemic brain injury in rodents. Stroke 41(2): 357-362. *Equal contribution.
Samanta J, Burke GM, McGuire T, Pisarek AJ, Mukhopadhyay A, Mishina Y and Kessler JA (2007). Bmpr1a signaling determines numbers of oligodendrocytes and Calbindin-expressing interneurons in the cortex. Journal of Neuroscience 27(28): 7397-7407.
Samanta J and Kessler JA (2004). Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation. Development 131(17): 4131- 4142.