4 YEAR PhD IN NEUROSCIENCE
Kris Jessen & Rhona Mirsky
Department of Cell and Developmental Biology
Development, differentiation and de-differentiation of peripheral glial cells
Peripheral nerve provides a simple model for studying the cell-cell signals, cytoplasmic pathways and transcription factors that shape mammalian development. It also provides a special opportunity to study neural repair and regeneration following injury. Work in this laboratory is aimed at understanding how multipotent neural crest cells are biased towards the Schwann cell lineage, how such cells become lineage committed, and what factors regulate their differentiation to myelin forming cells and their de-differentiation after nerve injury. A main focus of our studies involves understanding how transcription factors such as c-Jun and signalling molecules such as Notch regulate commitment of Schwann cells to myelination during development and de-myelination following injury. A variety of molecular and cellular methods (in situ hybridisation, RT-PCR, cDNA cloning, immunohistochemistry, cell culture) are routinely applied to nerves from normal and transgenic animals (rats and mice).
We are currently interested in the role of the transcription factor c-Jun in the control of Schwann cell de-differentiation after nerve injury and in animal models of inherited nervous system diseases. We have found that lack of c-Jun has profound effects on the behaviour of injured Schwann cells, causing them to de-myelinate and de-differentiate more slowly than usual. This in turn has effects on the recruitment of macrophages and on the re-growth of axons into the damaged nerve. Currently we would like to understand at the molecular level how c-Jun controls the intrinsic Schwann cell response to injury, and how c-Jun controls the critical communication between Schwann cells and their environment in regenerating nerves, especially macrophages and growing axons. We have also found that the signalling molecule Notch speeds up the transition of Schwann cell precursors to Schwann cells and that it regulates Schwann cell proliferation and myelination. Using mice that either over-express or lack components of the Notch pathway, we are investigating how Notch acts to negatively regulate myelination both in development and after nerve injury. Possible links between the actions of c-Jun and Notch are also being explored.
Woodhoo A, Sahni V, Gilson J, Setzu A, Franklin RJM, Blakemore WF, Mirsky R and Jessen KR (2007)
Schwann cell precursors: a favourable cell for myelin repair in the Central Nervous System.
Sharghi-Namini S, Turmaine M, Meier C, Sahni V, Umehara F, Jessen KR and Mirsky R (2006)
The structural and functional integrity of peripheral nerves depends on the glial-derived signal desert hedgehog.
J Neurosci 26:6364-63
Arthur-Farraj P, Mirsky R, Parkinson DB and Jessen KR (2006)
A double point mutation in the DNA-binding region of Egr2 switches its function from inhibition to induction of proliferation: A potential contribution to the development of congenital hypomyelinating neuropathy
Neurobiol Dis 24:159-169.
D'Antonio M, Droggiti A, Feltri ML, Roes J, Wrabetz L, Mirsky R, Jessen KR (2006)
TGFbeta type II receptor signaling controls Schwann cell death and proliferation in developing nerves.
J Neurosci 26:8417-27.
Wanner IB, Guerra NK, Mahoney J, Kumar A, Wood PM, Mirsky R and Jessen KR (2006)
Role of N-cadherin in Schwann cell precursors of growing nerves.
Parkinson DB, Bhaskaran A, Droggiti A, Dickinson S, D'Antonio M, Mirsky R and Jessen KR (2004)
Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death.
J Cell Biol 164:385-394.
R. Mirsky, K.R Jessen. (1996)
Schwann cell development, differentiation and myelination.
Neurobiology, 1996, 6, 89-96.
Z. Dong., A. Brennan, N.Liu, Y.Yarden, G. Lefkowitz, R. Mirsky and K.R. Jessen, (1995)
Neu differentiation factor is a neuron-glia signal and regulates survival proliferation and maturation of rat Schwann cell precursors.
Neuron, 1995, 15, 585-596.
G.Zoidl, A.D. Blanchard, C.Zoidl, Z. Dong, A. Brennan E.Parmantier, R. Mirsky and K.R. Jessen. J ()
Identification of transcriptionally regulated mRNAs from mouse Schwann cell precursors using modified RNA fingerprinting methods.
J Neurosci. Res., 49, 32-42.