Stower, M.J.; (2012) Early steps in neural induction. Doctoral thesis , UCL (University College London).

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Abstract

Neural induction is the instructive interaction whereby signals emitted from the organizer direct cells in the ectoderm to a neural fate and thereby to form the neural plate. Recent work in many labs has suggested that it involves a hierarchy of molecular events. Here, I investigate the earliest steps in the neural induction cascade and the signals that define them. Many genes expressed during the neural induction cascade have been shown to be regulated by FGF. However the signals that induce three of the genes, Bert, TrkC and Obelix, are unknown. I therefore tested candidate signalling molecules by misexpression analysis. While Obelix is also regulated by FGF, none of many factors tested, including FGF, retinoic acid, somatostatin, noggin, insulin, and increasing intracellular calcium were able to induce expression of TrkC or Bert. BMP also plays an important role in neural induction, I therefore studied how cells may integrate TGFβ signalling through Smad1 and Smad2. I used a BiFCo approach to investigate Smad protein binding interactions in culture and in vivo, however this did not turn out to be a useful method for this question. Finally I investigated the ground-state of the epiblast at the start of the neural induction cascade. Culture of early epiblast explants showed, unexpectedly, that cells initially enter a state similar to that of the neural plate border, confirmed by their subsequent differentiation into lens. This correlates with the finding that BMP signalling in vivo only affects cells of the neural plate border region and suggests why explants can be neuralized by BMP. Overall, the experiments reveal a hitherto unknown importance of a neural border cell-state, and suggest that lens is the ground state at the start of the neural induction cascade.

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