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The developmental logic of trigeminal sensory neurons

Reference	BB/J015261/1
Principal Investigator / Supervisor	Professor Anthony Graham
Co-Investigators / Co-Supervisors	Professor Michiel Basson, Dr David Chambers
Institution	King's College London
Department	Developmental Neurobiology
Funding type	Research
Value (£)	372,933
Status	Completed
Type	Research Grant
Start date	01/09/2012
End date	31/12/2015
Duration	40 months

Abstract

The sensory neurons that contribute to the trigeminal nerve have a complex developmental history. Those in the trigeminal ganglion derive from three distinct embryonic populations - the ophthalmic placode, the maxillomandibular placode and the cranial neural crest. Furthermore, the trigeminal proprioceptive sensory neurons are born within the dorsal midbrain, and although their embryonic origin is uncertain, evidence suggest that they may be CNS derived. This situation stands in marked contrast to the development of the sensory neurons of the trunk. These are exclusively derived from the neural crest and their development has been well characterised. The significance of the developmental complexity of trigeminal sensory neurons has never been uncovered and it is with this issue that this proposal is concerned. We will use a variety of techniques in both mouse and chick embryos to address this issue These will include fate mapping the different embryonic populations that contribute to the trigeminal using electropration in chick and genetic labelling in mice, misexpression of genes using electroporation in chick and the use of mouse mutants to study the role of motor neurons in directing proprioceptive axons to exit the brain and microarray analysis to explore commonalities and differences between sensory neurons with different embryonic origins. Hypotheses 1 - that sensory neurons of the trigeminal ganglion with distinct developmental origins have distinct central and peripheral projections 2 - that the neurons of the MTN are CNS derived and that their development is intrinsic to neural tissue with a midbrain identity 3 - That sensory neurons of similar modalities with different embryonic origins have distinct developmental paths 4 - that the trigeminal motor axons direct the MTN axons to run in the mandibular ramus

Summary

Sensory neurons relay information about our external environment to our central nervous system. The sensory neurons that project to our face and jaws, form part of trigeminal nerve, whose name derived from the fact that it has 3 branches; one branch projects to the forehead region, one to the upper jaw and one to the lower jaw. Many of these neurons are concerned with relaying information about heat, pain, and touch from the head to brain. Another group of trigeminal sensory neurons is additionally concerned with spatial information about the position of our jaw, which is important for mastication and speech. This same situation is seen in all jawed vertebrates. We know a lot about how sensory neurons develop in the trunk. They are found in the dorsal root ganglia, which form alongside the spinal cord. They arise from a single embryonic population called neural crest cells during early development and progress through a well-studied path to differentiate as sensory neurons. The situation with the trigeminal nerve is very different however - it is much more complex. The sensory neurons that are concerned with heat, pain and touch are found in the trigeminal ganglion, which does lie alongside the brain, but rather than being derived from a single embryonic population that are derived from 3 distinct populations. Many are derived from thickenings of the embryonic skin, the ophthalmic placode and the maxillomandibular placodes, as well as some from neural crest cells. In stark contrast to what is seen in the trunk, the neurons that transfer information about the spatial position of the jaw are not found in ganglia beside the central nervous system but are rather found within the brain itself. In the trunk, the neurons that monitor the position of the limbs also reside in the dorsal root ganglia. The aim of this research is to understand the significance of the developmental complexity that we find in the trigeminal system and to test the hypothesis that the embryonicorigin of trigeminal sensory neurons matters. Preliminary data suggests that trigeminal sensory neurons send axons to different regions of the head. If this were true for all trigeminal neurons of different origins then this would allow us to demonstrate previously unknown complexity within the trigeminal system. This would have an impact for our understanding of the adult and aging situation. We will determine why the neurons that monitor the positioning of the jaw are sitting within the brain. We will also conduct an in depth comparison between the development of trigeminal and trunk sensory neurons to help us gain insights into the commonalities and differences that exits in the programme that lead to the formation of sensory neurons. Finally, we will also test if the motor neurons that control the movement of the jaw are also important in leading the axons of the sensory neurons that monitor its position to their correct location and how this is achieved

Impact Summary

Our work will have a number of academic impacts. It will advance worldwide academic knowledge in the area of sensory neuron development and vertebrate head development and evolution. Our work will provide an important knowledge base that will allow academics to compare sensory neuronal development in the trunk with that in the trigeminal and to thus identify commonalities and differences that exits in sensory neuronal differentiation. It will also uncover the significance of the developmental complexity of the trigeminal and how that relates generally to head development and evolution and thus inform evolutionary scenarios. It will also have resonance with those in other fields including those interested in the adult and aging nervous system. We predict that the developmental complexity of the trigeminal will underpin different features identified in the adult trigeminal. It will contribute to the health of academic disciplines including developmental biology and evolutionary developmental biology. It will help train highly skilled researchers at the post-doctoral, post-graduate and undergraduate levels through engagement in the project. It will feed into improvements in the teaching and learning of undergraduate science and medical students as it will allow us to use this work as an example of how research is approached and conducted. Our work will have a number of economic and societal impacts. Through talks to schoolteachers and 6th form students we will work to engage the public how biological research is conducted, the methods used and the types of conclusions that one can arrive at. This will also engage them in think about ethical issues, such as the use of animals in research and the potential benefits of this type of research. Our work may have impact for improving health and well-being. If we find that trigeminal neurons with different embryonic origins project have distinct projections to different areas of the head then this could feed into to our understanding of trigeminal neuropathies. Through our analysis of the commonalities and differences that exist in the development of sensory neurons of different origin in the trigeminal versus those of the trunk we could identify some important specific regulators of sensory neurons development and function which could in turn lead to commercial exploitation.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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