TWIST1: a subtle modulator of neural differentiation and neural tube formation
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Date
06/07/2013Author
Nistor, Paul Andrei
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Abstract
The central nervous system is formed from epiblast precursor cells through
Neurulation. Neural induction can be studied in its main aspects in vitro. However,
the process is poorly understood, especially in regard to when and how a cell
becomes specified, and then committed, to be a neural cell. It is, on the other hand,
well established that neural formation requires absence or, inhibition of the BMP
signalling both in vivo and in vitro.
ID1 is a direct target of BMP signalling with major influence on in vitro neural
differentiation. A cDNA library screen, looking for transcription factors negatively
regulated by ID1, reported TWIST1, along with only two other proteins. Twist1
expression is upregulated during in vitro neural differentiation. Furthermore, targeted
deletion of Twist1 has dramatic consequences on anterior neural development. Twist1
knock-out mice fail to form the closed neural tube in the prospective brain, followed
by exencephaly and, early embryonic death.
In this thesis I investigate the influence on in vitro neural differentiation of a
TWIST1 constitutively active form, insensitive to ID1 inhibition. I report that this
transcriptionally active TWIST1 accelerates neural differentiation, in vitro and, biases
it, towards dorsal phenotypes. I provide, for the first time, evidence for Twist1
expression in the neural tissue, observed weakly in a restricted domain, temporally
and spatially, in the dorsal part of the neural tube. I propose a new model for TWIST1
influence at this level. I also investigate how TWIST1 actions depend on levels of
expression and dimer choice. I found that, TWIST1 can exert its neural modulating
actions only at low levels, as high levels divert a cell fate towards non-neural
lineages.