Interaction between neurons, glia and target field cells in regulating the survival of cranial sensory neurons

1. AIMS: During embryonic development, most cutaneous sensory neurons depend for their survival on a supply of NGF synthesised in the skin. NGF promotes survival by binding to the trkA receptor tyrosine kinase whose signalling is modulated by the common neurotrophin receptor p75. trkA is expressed in trigeminal neurons shortly after axons reach their targets and NGF expression begins with the arrival of the earliest axons. This thesis was aimed at investigating interactions between neurons and targets using the trigeminal ganglion and its maxillary target field. Specifically, it assessed a. whether the induction and subsequent developmental changes in trkA mRNA seen in the ganglion in vivo are intrinsically regulated or dependent upon extrinsic signals, and whether N regulation ofNGF expression in the target field is influenced by the innervating ganglion. Further, it was aimed at c. assessing the importance of the trkA, trkB (BDNF-receptor) and full-length and truncated p75 neurotrophin receptors in promoting survival in the developing trigeminal ganglion, and d. determining the role of non target-related survival-mechanisms by Schwann cell precursors on trigeminal ganglion neurons and other cranial sensory ganglia, namely the nodose, dorsal root and superior cervical ganglia.2. METHODOLOGY: a. and b. Ganglion-target interactions and their effect on trkA and NGF expression were assessed using cultures of trigeminal ganglia and its target fields alone or in combination. Complementary approaches used knockout mice that increased or decreased the neuronal population in the trigeminal ganglion in vivo. c. The role of the neurotrophin receptors trkA, trkB and p75 in trigeminal neuron survival was assessed using knockout mice, including double knockout mice for trkA and trkB. d. The role of Schwann cell precursors in the survival of different populations of cranial sensory neurons was assessed using ErbB3 knockouts, which lack these cells.3. MAIN FINDINGS: a. Upregulation of trkA mRNA expression in the trigeminal ganglion appears to follow an intrinsic programme, with in vitro expression levels mimicking levels in vivo. However, extrinsic signals from the target-fields have a negative effect on trkA expression in vitro, b. Early target field NGF mRNA expression was positively influenced by ganglion innervation in vitro, and was significantly lower in the early target fields of embryos lacking trigeminal neurons early in development in vivo. c. Double trkA/trkB knockouts displayed neuronal death in the trigeminal ganglion, in a pattern suggesting that during certain phases in development there are subsets of neurons, which can survive with either one or the other receptor, whereas at other developmental stages both receptors are required. Neuronal losses in different p75 mutant embryos suggest a survival-promoting effect of p75 early in embryonic development, with truncated p75 having a role earlier in development than fulllength p75. d. Neuronal deficiencies in ErbB3-t- embryos support the idea that populations of cranial sensory neurons differ in their survival-requirement for Schwann cell precursors early in development, with early trigeminal and dorsal root neurons being more dependent on this support than early nodose neurons.4. SYNTHESIS AND CONCLUSIONS: a. and b. The results suggest that in addition to intrinsic mechanisms of regulation, trkA and NGF expression are subject to complex reciprocal interactions between the trigeminal ganglion and its target fields early in development. The control of survival of neurons during development may thus involve more than the restricted supply of survival factor from the target field, c, Sequential dependence of sensory neurons on one or more survival factor probably serves to increase survival to maximize the 'choice' of the target field during naturally occurring cell death, and to establish heterogeneity in the ganglion, d. Differences in the sensitivity of cranial sensory neurons to trophic support by Schwann cell precursors during early development are presumably related to the distance different populations grow to their target fields. Thus, in addition to survival provided by the target field, neurons appear to depend on survival signals from surrounding cells between the ganglion and the target field.Overall, these data support modifications to the way we should think about the way target derived signals regulate the survival of peripheral neurons. Rather than being a passive receipt of a restricted supply of NGF from the target field, it appears that complex target-ganglion interactions are involved, as well as input from other neurotrophic factors, either separately or in synergy with NGF, and input from non-target cells, such as Schwann cell precursors

Peripheral nerve glia as multipotent progenitors in craniofacial development

Craniofacial development is complex. Numerous populations of progenitor cells coordinate activities to produce an array of highly integrated tissues inside the developing head. However, it is not clear how some key multipotent progenitors continue to exist in late developing head compartments. The general hypothesis of this thesis is focused around the idea of an embryonic infrastructure represented by peripheral nerves that serves as a niche for glial multipotent neural crest-like cells. The nerve-adjacent glial cells can change their fate and be recruited in a targeted way to produce tissues at remote destinations during fast growth, development and regeneration. Results presented in this thesis explain how the nerves contribute pulp cells and matrix-producing cells of odontoblast lineage to the developing and growing tooth. Glial cells as an unexpected progenitor source give rise to almost half of all pulp cells and odontoblasts in the growing incisor. Furthermore, lineage tracing with colour-coding of individual recombination events allowed us to discover new aspects of tooth development and coordination between pulp cell lineage and odontoblasts. Another important component of the craniofacial compartment, the parasympathetic nervous system that targets glands in the head, is crucial for "rest-and-digest" or "feed and breed" activities especially during eating, salivation and lacrimation. Importantly, neurons of the autonomic parasympathetic nervous system are located very close to or inside the tissues they innervate and appear late in embryonic development. The discrepancy in developmental timing raised new questions: how do early neural crest-derived progenitors of parasympathetic neurons reach their destinations, and how do they acquire neuronal properties in situ? Furthermore, what is the nature of those progenitor cells? Our results clearly demonstrate that cells of glial origin located in the peripheral nervous system possess multipotency and gives rise to parasympathetic neurons during later developmental stages. Peripheral glial cells arrive to late-developing tissues on the pioneer presynaptic nerve fibres. Subsequently, some glial cells change fate, navigate for short distances and then convert into neurons and satellite cells of parasympathetic ganglia. Our conclusions redraw a fundamental principle on how the peripheral nervous system develops and provide a new type of logic, where both the cellular elements, as well as, the wiring are solved by a simple deposition of the postsynaptic elements from the presynaptic. During our work we used a wide spectrum of approaches including advanced genetic tracing with multicolor reporters, analysis of numerous mouse mutants, in vitro cell cultures and 3D imaging of developing embryos. We have applied both genetic and surgical ablation techniques to the peripheral nerves and investigated targeted recruitment of glia from the nerves in each case. Peripheral glia represents a novel amenable source of multipotent progenitor cells with putative regenerative potential that in the future might be applied for the treatment of congenital craniofacial pathologies, trauma cases or used for aesthetic body treatments

Activity-dependent refinement of the developing visual system. A comparative study across retinal ganglion cell populations and target nuclei

The formation of the mammalian visual system is a complex process that takes place in several phases and includes neurogenesis, axon guidance, axonal refinement and circuit assembly. The last stage of this process occurs after birth but before eye opening. During this period, axon terminals from retinal ganglion cells (RGCs) first extensively arborize in the different visual nuclei and then refine and establish appropriate connections. It is known that the spontaneous activity generated in the immature retina during perinatal ages plays an important role in this axonal refinement process but it is not clear to what extent such retinal activity differentially influences the refinement of the distinct populations of RGCs when they project to specific visual nuclei. To address this issue we have generated conditional mouse lines to alter spontaneous activity in different populations of RGCs and we have analyzed the projection patterns of RGCs in different visual nuclei in each of these mouse lines. Our results show that the alteration of spontaneous activity in RGCs affects axon refinement in the image-forming nuclei such as the lateral geniculate nucleus and the superior colliculus, supporting previous publications. Interestingly, we also observed that, although to a lesser extent than in the image-forming nuclei, retinal spontaneous activity correlation is important for the refinement of RGC axons in the non-image-forming nuclei such as the pretectal olive nucleus or the suprachiasmatic nucleus

Aerospace medicine and biology: A continuing bibliography with indexes, supplement 218, April 1981

This bibliography lists 161 reports, articles, and other documents introduced into the NASA scientific and technical information system in March 1981

Cyclical fate restriction:A new view of neural crest cell fate specification

Neural crest cells are crucial in development, not least because of their remarkable multipotency. Early findings stimulated two hypotheses for how fate specification and commitment from fully multipotent neural crest cells might occur, progressive fate restriction (PFR) and direct fate restriction, differing in whether partially restricted intermediates were involved. Initially hotly debated, they remain unreconciled, although PFR has become favoured. However, testing of a PFR hypothesis of zebrafish pigment cell development refutes this view. We propose a novel ‘cyclical fate restriction’ hypothesis, based upon a more dynamic view of transcriptional states, reconciling the experimental evidence underpinning the traditional hypotheses.</p

Neural Mechanisms for Information Compression by Multiple Alignment, Unification and Search

This article describes how an abstract framework for perception and cognition may be realised in terms of neural mechanisms and neural processing. This framework — called information compression by multiple alignment, unification and search (ICMAUS) — has been developed in previous research as a generalized model of any system for processing information, either natural or artificial. It has a range of applications including the analysis and production of natural language, unsupervised inductive learning, recognition of objects and patterns, probabilistic reasoning, and others. The proposals in this article may be seen as an extension and development of Hebb’s (1949) concept of a ‘cell assembly’. The article describes how the concept of ‘pattern’ in the ICMAUS framework may be mapped onto a version of the cell assembly concept and the way in which neural mechanisms may achieve the effect of ‘multiple alignment’ in the ICMAUS framework. By contrast with the Hebbian concept of a cell assembly, it is proposed here that any one neuron can belong in one assembly and only one assembly. A key feature of present proposals, which is not part of the Hebbian concept, is that any cell assembly may contain ‘references’ or ‘codes’ that serve to identify one or more other cell assemblies. This mechanism allows information to be stored in a compressed form, it provides a robust mechanism by which assemblies may be connected to form hierarchies and other kinds of structure, it means that assemblies can express abstract concepts, and it provides solutions to some of the other problems associated with cell assemblies. Drawing on insights derived from the ICMAUS framework, the article also describes how learning may be achieved with neural mechanisms. This concept of learning is significantly different from the Hebbian concept and appears to provide a better account of what we know about human learning

Primary sensory map formations reflect unique needs and molecular cues specific to each sensory system [version 1; peer review: 2 approved]

Interaction with the world around us requires extracting meaningful signals to guide behavior. Each of the six mammalian senses (olfaction, vision, somatosensation, hearing, balance, and taste) has a unique primary map that extracts sense-specific information. Sensory systems in the periphery and their target neurons in the central nervous system develop independently and must develop specific connections for proper sensory processing. In addition, the regulation of sensory map formation is independent of and prior to central target neuronal development in several maps. This review provides an overview of the current level of understanding of primary map formation of the six mammalian senses. Cell cycle exit, combined with incompletely understood molecules and their regulation, provides chemoaffinity-mediated primary maps that are further refined by activity. The interplay between cell cycle exit, molecular guidance, and activity-mediated refinement is the basis of dominance stripes after redundant organ transplantations in the visual and balance system. A more advanced level of understanding of primary map formation could benefit ongoing restoration attempts of impaired senses by guiding proper functional connection formations of restored sensory organs with their central nervous system targets