Trevers, KE; (2015) A Cascade of Molecular Events During Neural Induction. Doctoral thesis , UCL (University College London).

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Abstract

Neural induction is the process by which a region of ectoderm acquires a neural identity and forms the neural plate. A popular explanation for neural induction is the “default model”. This proposes that non-neural cells are specified as epidermal by BMP expression and that inhibition of this signal at the end of gastrulation is sufficient to induce neural fate. Although this model is attractive in its simplicity, accumulating evidence suggests a more complex scenario, where neural induction comprises a series of sequential events and multiple signals. However the details of this hierarchy are unclear, as are the specific contributions of different signalling pathways. Using a range of known markers, we first characterised the progression of neural induction. The earliest responses occur in competent cells within 3h of exposure to a grafted organizer, but 9-12h are required before cells become committed to a neural fate. To identify all transcriptional responses to neural induction during this time-course, an RNA-Seq screen was conducted. It identified 482 differentially expressed transcriptional regulators. After verifying the expression of 166, we confirm that the screen accurately predicts events that occur in the normal embryo during neural induction. Distinct markers define the specification of key states before cells adopt neural commitment. Furthermore, transitions between these states are probably regulated by multiple layers of transcriptional repression and activation. Therefore neural induction must occur as a cascade of molecular events. We also demonstrate that FGF signalling makes a major contribution to the onset of neural induction by inducing transcription factors and chromatin modifiers. These are normally expressed in the pre-streak embryo, providing further evidence that neural induction begins before gastrulation. This pre-neural state is transcriptionally similar to the neural plate border but is also heavily associated with pluripotency -perhaps suggesting that FGFs function to induce a multipotent “pre-neural/pre-border” state.

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