Hashemi, HM; (2015) The Regulation of spinal neurogenesis by PTPγ. Doctoral thesis , UCL (University College London).

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Abstract

RPTPs have striking patterns of expression within the neural tube; raising interesting questions as to their role in the development of this structure. PTPγ expression is initially observed in the first born neurons and this expression domain progressively expands to the lateral motor columns and intermediate zone of differentiating neurons. Short hairpin encoding RNAi constructs were generated against PTPγ, which effectively knocked down this gene in vitro and in ovo. Analysis of silenced embryos through neuronal markers presented a range of phenotypes. The most striking was a dorsoventral truncation of the neural tube arising from a loss of LIM-HD expressing cells not observed among controls. During the onset of neurogenesis, a loss of Lim1/2/3, Islet1/2, and Mnr2/Hb9 positive cells was observed. At later stages, Islet1/2 cells showed no such sustained effect essentially recovering. A further heterotopic phenotype was observed with mislocated neurons located ectopically in the ventricular lumen, that were Islet1/2 and Nkx2.2 positive but never Lim1/2/3. The targeted regions showed a significant decrease in apoptosis suggesting newly born neurons were dying before reaching their pool specific domains. A reduction in the proliferative capacity in the ependymal zone demonstrated by Histone3 activity. Over expression of PTPγ showed a similar reduction in LIM-HD expression however no overall change in S-Phase was observed yet cells at M Phase were reduced with no apoptosis detected through Caspase3 activity. The data suggests PTPγ silencing may result in a failure of Lim1/2/3 cells to reach their final destinations and acquire LIM-HD identities, implicating this gene in the development of inter and motor neuron populations. Preliminary RNAi experiments against PTPσ show a reduction in LIM-HD fated cells and a triggering of the apoptosis programme along with a reduction in number of mitotically active cells. This is consistent with a potential role for PTPs during neurogenesis and the birth of the first neuronal populations in the neural tube.

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