Role of Histone deacetylase in motor neuron regeneration downstream of immune system activation

Tess McCann, Leonardo Cavone, Catherina G. Becker, Thomas Becker

Centre for Neuroregeneration, The University of Edinburgh, The Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB

After spinal cord lesion, zebrafish regenerate motor neurons. We know that immune system activation is needed for regenerative neurogenesis (1) , but the downstream changes in spinal progenitor cells that allow a switch to regenerative neurogenesis are unclear. Histone deacetylase 1 (Hdac1) has been found to promote developmental neurogenesis by regulating the expression of transcription factors involved in neuronal specification (2) and important signalling pathways such as Notch (3) and Sonic Hedgehog (4). These pathways have known roles in spinal cord regeneration (5,6). Increased Hdac1 activity in spinal progenitor cells following immune system activation could therefore be a mechanism that facilitates the integration of these different pathways, which leads to the successful regeneration in zebrafish.

We find that hdac1 expression levels were increased in the spinal cord progenitors after a lesion. This upregulation depended on the presence of microglia/macrophages, as hdac1 upregulation was not observed in if8-/- mutant, which lack these immune cell types. To test whether Hdac1 function was necessary for neuroregeneration, pharmacology inhibitors the pan inhibitor Trichostatin A and a class I-specific inhibitor Mocetinostat were used. It was found that when Hdac1 was inhibited during regeneration there was a significant decrease in the numbers of new motor neurons. To allow conditional and cell type-specific manipulations of Hdac1 in the progenitors in the spinal cord, we are now using the TetOn system. Results so far suggest an important role of Hdac1 in successful motor neuron regeneration in zebrafish downstream of immune system activation.

References

  1. Ohnmacht, J. et al., 2016. . Development, p.dev.129155-.
  2. Harrison, M.R.M. et al., 2011. BMC genomics, 12, p.24.
  3. Cunliffe, V.T., 2004.. Development, 131(12), pp.2983–95.
  4. Canettieri, G. et al., 2010. Nat Cell Biol, 12(2), pp.132–42.
  5. Dias, T.B. et al., 2012. J. Neurosci, 32(9), pp.3245–52.
  6. Reimer, M.M. et al., 2009. J. Neurosci, 29(48), pp.15073–15082.

Funded by:  Supported by an MRC DTG studentship (to TMC) and the BBSRC (CGB, TB

* entered into the PhD student poster competition