Plasticity & Maintenance: How the nervous system interacts with its environment

Unforeseen aspects of expression patterns of terminal differentiation genes that we discovered over the years have drawn us into areas of neurobiology that go beyond development and provided us with insights about how the environment interacts with individual neurons and the nervous system as a whole:

(a) How neurons perceive environmental taste cues
The left/right asymmetric expression of receptor-type guanylyl cyclases (rGCs) in the ASE(L/R) salt receptor neurons, as well as the generally poorly understood mechanisms of salt detection in any system ignited our interest in studying rGCY function (Figure 1). We have found that individual rGCYs are required for the processing of specific taste cues [1]. Domain swap experiments demonstrated that their extracellular domain is required for specific sensory responses, supporting the view that they may work as salt receptors (unpubl.data).

(b) How neuronal anatomy and circuitry is modulated by environmental conditions
Our analysis of expression patterns of terminal differentiation features of serotonergic neurons has led us to discover that environmental oxygen levels (i) impact on the migration and axon pathfinding of serotonergic neurons[2] and (ii) induce a rerouting of chemosensory information through a novel, serotonin- and neuropeptide-mediated circuit to ensure the robustness of the gustatory response under adverse conditions[3](Figure 2). We are currently investigating how an enviromentally and hormonally controlled altered life state of the worm, the dauer state, impacts on the execution of terminal differentiation programs in the nervous system.

(c) Facing environmental challenges: How the anatomy of the nervous system is maintained
Another gfp-based expression survey of terminal differentiation genes had led us to identify an unusual family of small, secreted Ig domain proteins (ZIG proteins), required to maintain the overall structural organization of the nervous system by counteracting environmental forces (generated by movement of the animal) that mechanically dislocate neuronal structures[4-7](Figure 3). These findings prompted us to search for more molecules with roles in maintaining nervous system architecture, leading us to the identification of maintenance roles of the FGF receptor egl-15 [8], the IgCAM sax-7 [9] and the extracellular matrix protein dig-1 [10].

Figure 1:

Figure 2:

Figure 3:

Figure legends:

Figure 1: Left/right asymmetric expression of receptor-type guanylyl-cyclases in the ASEL/R neuron pair.

Figure 2: Model for hypoxia-enhanced sensory perception in C. elegans. In normoxic conditions, the ASE neurons are the major contributors to gustatory behavior, with the ADF and ASG neurons playing a minor role (top schematic). After prolonged exposure to hypoxic stress, the neuronal circuit for gustation is reprogrammed to enable enhanced responsiveness to the environment. This reprogrammed behavior is co-ordinated by both 5-HT and neuropeptide signaling and utilizes known (ADF and ASG), and novel (M4, AQR, PQR and URX) cellular mediators of gustation.

Figure 3: Maintenance of neuronal architecture in the nervous system of C. elegans.
A. The majority of the 302 neurons (in red) of the worm are organized into major ganglia in the head and tail, as well as into fascicles such as the ventral nerve cord. This organization is established during embryogenesis and retained throughout life.

B. Schematic representation of the head of a worm, with neurons in head ganglia (in red). Throughout larval and adult stages, the worm swims in its environment foraging for food and feeds itself as a result of the motions of its pharynx, which pumps food towards the gut. These life-long motions exert considerable mechanical strain on the neurons situated near the pharynx and lead to the progressive displacement of neurons in the absence of dedicated neuronal maintenance mechanisms (C).

C. Example of maintenance defects in head ganglia. In wild-type worms, the cell bodies of a subset of chemosensory neurons of the head are located posterior to the nerve ring (indicated by a white arrow head). This chemosensory architecture develops in embryogenesis and persists throughout life. In maintenance mutants such as sax-7 or dig-1, the chemosensory neurons develop completely normally and are indistinguishable form wild type at birth, but later become progressively displaced (red arrow, anterior to the nerve ring).

D. Diagram of the ventral portion of a cross section through a worm at birth, first larval stage, and adulthood. The ventral nerve cord develops largely embryonically, with axons organized into the left and right fascicles on either side of a midline; the midline is initially constituted of motor neuron soma that are aligned along the a/p axis and postembryonically becomes further elaborated by an evagination (“hypodermal ridge”) of epidermal tissue. The ventral nerve cord is ensheathed by basement membrane material (shown in blue). This separate organization of the fascicles of the ventral nerve cord is maintained throughout life, despite the addition of neurons and axons during the first larval stage (in yellow). However, this arrangement can de disturbed, in the absence of dedicated maintenance factors, as a result of the mechanical strain exerted by the locomotion movements of the worm (E). The failure of maintaining the ventral nerve cord architecture occurs at a time right after birth (first larval stage) when additional axons and neurons are added and when the hypodermal ridge – an insurmountable obstacle in adult animals – has not yet been fully elaborated.

E. Example of maintenance defects in the ventral nerve cord. In wild-type worms, the axons of the two PVQ neurons project into the left and the right fascicles of the ventral nerve cord, during embryogenesis. These axons remain in their precise position within the ventral nerve cord throughout life, despite incessant movements of locomotion. In zig-4, egl-15, sax-7 and dig-1 mutants, these axons develop normally and are born identical to the wild type. However, during the first larval stage, mechanical strain from locomotion leads specific axons to flip over the ventral midline to the other fascicle of the ventral nerve cord. Small white dots are background autofluorescence from the gut.
Taken from [7].

Bibliography:

1. Ortiz, C.O., et al., Lateralized gustatory behavior of C. elegans is controlled by specific receptor-type guanylyl cyclases. Curr Biol, 2009. 19(12): p. 996-1004.

2. Pocock, R. and O. Hobert, Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans. Nat Neurosci, 2008. 11(8): p. 894-900.

3. Pocock, R. and O. Hobert, Hypoxia activates a latent circuit for processing gustatory information in C. elegans. Nat Neurosci, 2010. 13(5): p. 610-4.

4. Aurelio, O., D.H. Hall, and O. Hobert, Immunoglobulin-domain proteins required for maintenance of ventral nerve cord organization. Science, 2002. 295(5555): p. 686-90.

5. Benard, C. and O. Hobert, The secreted Ig domain proteins ZIG-5 and ZIG-8 genetically interact with L1CAM/SAX-7 to maintain neuronal soma position. submitted, 2011.

6. Benard, C., et al., The small, secreted immunoglobulin protein ZIG-3 maintains axon position in Caenorhabditis elegans. Genetics, 2009. 183(3): p. 917-27.

7. Benard, C. and O. Hobert, Looking beyond development: maintaining nervous system architecture. Curr Top Dev Biol, 2009. 87: p. 175-94.

8. Bülow, H.E., T. Boulin, and O. Hobert, Differential functions of the C. elegans FGF receptor in axon outgrowth and maintenance of axon position. Neuron, 2004. 42(3): p. 367-74.

9. Pocock, R., et al., Functional dissection of the C. elegans cell adhesion molecule SAX-7, a homologue of human L1. Mol Cell Neurosci, 2008. 37(1): p. 56-68.

10. Benard, C.Y., et al., DIG-1, a novel giant protein, non-autonomously mediates maintenance of nervous system architecture. Development, 2006. 133(17): p. 3329-40.