Harris, Brett Stuart; (2001) Zinc-finger transcription factors in the Schwann cell lineage. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Myelin forming and non-myelin forming Schwann cells are the major glia within peripheral nerves. Recent studies have revealed the importance of the transcription factors Sox10, Pax3, Krox-20 and Oct-6 in Schwann cell development. This work describes one novel Schwann cell zinc-finger transcription factor, Zfp-57, and investigates the phenotype of Schwann cells deficient in another, Krox-24, with a view to discovering a function for these genes in Schwann cells. Zfp-57 is expressed in nerves from embryo day 12 to adult and is present in Schwann cell nuclei. To investigate whether Zfp-57 plays a role in myelination, Zfp-57 cDNA was overexpressed in Schwann cells. No effects were detected on Schwann cell differentiation towards a myelin phenotype, suggesting that Zfp-57 may not be involved in this process I undertook a detailed investigation of nerves of Krox-24 null mutant and heterozygous mice in which expression of the LacZ gene is controlled by the Krox-24 promoter. Krox-24 activation occurs in late embryonic/early postnatal peripheral nerve development. In nerves, mRNA levels of typical Schwann cell molecules are normal, proliferation and the ultrastructural morphology is not affected. In regenerating nerves Krox-24 deficient Schwann cells down-regulate myelin genes and up-regulate molecules required for regeneration as efficiently as wildtype cells except for p75NTR mRNA, which is increased in Krox-24 deficient mice. Furthermore axonal regeneration occurs normally. Schwann cell death occurs developmentally and the effect of Krox-24 deficiency on this phenomenon has been investigated using TUNEL. 1 day after transection of newborn sciatic nerves cell death is elevated threefold in Krox-24-/- mice compared to wiltype littermates. In a low density culture assay where cell death is measured in the absence of autocrine Schwann cell survival factors, there is no difference between Krox-24 null cells and normal Schwann cells. Additionally cell death induced by TGFβ is unaltered.

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