Neural Induction

Deciding Neural Fate

The production of neural fated tissue begins with the organiser which prior to convergent extension induces the ectoderm to acquire a neural fate. This plate of cells induced to a neural fate will eventually fold up and fuse into the neural tube as well as neural crest cells. The neural tube will then go on to produce all the cells of the CNS whilst the neural crest will give rise to the peripheral nervous system (PNS).

Signals: the primary cause of embryonic neural fate.

The embryo needs to coordinate a vast number of processes and uses signals such as transcription factors to orchestrate these events. This includes signals from the organiser inducing the ectoderm into a neural fate. Experiments have highlighted how isolated ectoderm before it is exposed to these signals differentiates into skin, whilst after exposure to the signals it becomes neural. In the classic Spemann and Mangold experiments a “donor” organiser grafted to a second host produced a twined embryo. Therefore the over-expression of these molecules leads the induction of a secondary axis. 60 years after the organiser graft experiment, molecular biologists uncovered the nature of neural inducers and identified the signals as anti-BMP signals which arise from the Spemann organiser.

Richard Herling et al. (1995) took advantage of the fact that a UV irradiated embryo failed to develop a dorsal axis as the Nieukoop centre which induced the Spemann organiser is prevented from formation. They found that purified Noggin a transcription factor, was capable of inducing neural genes without inducing mesodermal genes and can also rescue UV irradiated embryos restoring the body axis. Another neural inducing molecule isolated is Chordin-a secreted signalling molecule expressed in the organiser. Neural inducing molecules do not all share the same sequence homology but they do all act in the same way; to inhibit BMPs.

BMP Signalling

All ectodermal cells make and secrete BMP (Bone Morphogenic Protein). BMPs are members of the TGF- β signalling family and diffuse out of the cell to act locally and bind to BMP receptors on adjacent cells. This triggers the BMP pathway which causes differentiation into epidermal ectoderm (skin). BMP causes the phosphorylation of type 2 and type 1 subunits of its receptor, which in turn causes the phosphorylation of the main transducers of BMP signalling-SMADS. The now phosphorylated R-SMADS complex with Co-SMADS and this moves to the nucleus where it binds to a specific DNA sequence- BMP Response element-to generate epidermalising transcription factors. In the absence of BMP, neural transcription factors are produced in a cascade that leads to the differentiation of cells into a neuron.

Neural inducers such as Chordin and Noggin work by diffusing into the same extracellular spaces as BMP and effectively compete for binding to BMP receptors so they remain un-activated. The deletion of Chordin and Noggin in mice has been shown to produce major effects on neural and head development as they both block BMP-4 receptor binding with high affinity.