Transient cell-cell interactions in neural circuit formation

Abstract

The wiring of the nervous system requires a complex orchestration of developmental events. Emerging evidence suggests that transient cell-cell interactions often serve as positional cues for axon guidance and synaptogenesis during the assembly of neural circuits. In contrast to the relatively stable cellular interactions between synaptic partners in mature circuits, these transient interactions involve cells that are not destined to be pre- or postsynaptic cells. Here we review the roles of these transient cell-cell interactions in a variety of developmental contexts and describe the mechanisms through which they organize neural connections.

Figure 1. Conceptual roles for transient cell–cell interactions in neural circuit formation

a | Guidepost cells as intermediate targets in axon guidance. A neuron (shown in orange) extends its axon and contacts a non-continuous set of guidepost cells (shown in green) in a sequential fashion. Each guidepost cell attracts the growth cone, allowing stepwise guidance of the axon. Examples of intermediate targets in axon guidance include the floor plate in the spinal cord and guidepost cells in the grasshopper limb. Molecules involved in intermediate-target axon guidance include the netrins, the Slits and sonic hedgehog (shh), and their respective receptors DCC, the Robos and BOC, as well as COMM and ROBO3. b | Cells as a scaffold for axonal tract formation. A neuron uses cells present along the path of the axonal trajectory as a substrate for axonal growth. Examples include ‘axon runway cells’ in leeches, LOT1a cells in the telencephalon, ‘corridor cells’ in the internal capsule and Bergmann glia in the cerebellum. Molecular factors implicated in this process include neuregulin 1 and its receptor ERBB4, and close homologue of L1 (CHL1). c | Cells as placeholders in neural circuit assembly. A presynaptic neuron (shown in red) extends its axonal process into the target field before the final postsynaptic targets are present and forms transient synapses onto placeholder cells (shown in green) in the target field (left-hand image). At a later developmental stage (middle image) the placeholder cell undergoes regulated cell death and the postsynaptic cell (shown in purple) is born and begins to extend its dendrite to the target field. Later in development (right-hand image) the postsynaptic dendrite grows into the target field and synapses are formed between pre- and postsynaptic cells. Examples of such placeholder cells include Cajal–Retzius cells in the hippocampus and subplate cells. d | Guidepost cells regulate the subcellular localization of synapses. Guidepost cells express membrane molecules (such as SYG-2) or secrete signals (such as Wnts or netrins) that promote or inhibit synaptogenesis in a defined subcellular region of the axon by binding their receptor (SYG-1, frizzled or DCC, respectively). Axon guidance is not affected by the guidepost cells themselves in this case. e | Guidepost cells as organizers of neural circuit formation. Guidepost cells can secrete signals (such as netrins) that both promote the local assembly of presynaptic specializations in the presynaptic axon and guide postsynaptic dendrites to their proper location.

Figure 2. Guidepost cells in grasshopper pioneer neuron axon guidance

The stereotyped axonal trajectory of Ti1 neurons. Ti1 axons reorient their trajectory at points of contact with specific cell types (Fe1, Tr1, Cx1 and P). Ablation of Cx1 cells causes Ti1 axons to wander and form ectopic branches. Figure is modified, with permission, from REF. ® (1986) Society for Neuroscience.

Figure 3. The floor plate as an intermediate target in axon guidance

a | A cross section of the developing vertebrate spinal cord. Commissural axons from only one side of the spinal cord are shown for simplicity. Commissural axons (shown in blue) are attracted to the floor plate (FP) by secretion of the chemoattractants netrins and sonic hedgehog (shh) (yellow shading). On crossing the midline, chemoattraction is silenced and commissural axons become receptive to the repulsive Slit cue (red shading), which is also secreted by the floor plate. This allows commissural axons to cross the midline only once. b | Molecular events that underlie commissural axon attraction to the floor plate. Netrins secreted from the floor plate bind their commissural axon-expressed receptor, DCC, allowing axon attraction towards the floor plate. The activities of the chemorepellent receptors ROBO1 and ROBO2 are inhibited by ROBO3.1, preventing repulsion of the axons away from the floor plate by Slits. c | Molecular events that coordinate the switch from attraction to repulsion in commissural axons. As commissural axons cross the floor plate, the activity of the netrin receptor DCC is inhibited by the Slit receptor ROBO1 through interactions between their cytoplasmic tails. Upregulation of ROBO3.2, ROBO1 and ROBO2 allows repulsion away from the midline through the chemorepellents the Slits. Data from REF. .

Figure 4. Radial glia and CD44+ cells in retinal axon guidance

Retinal ganglion cell (RGC) axons from one eye only are shown for simplicity. Ventral temporal (VT) RGC axons (shown in red) contact radial glia and are repelled from the midline to form the uncrossed projection. This repulsion is in part due to interactions between ephrin B2, expressed on radial glia, and its receptor, EPHB1, expressed on VT RGC axons. Non-VT RGC axons (shown in green) do not express EPHB1 and so cross the midline to form the contralateral projection. This crossing is dependent on CD44+ neurons located at the optic chiasm.

Figure 5. Bergmann glia direct stellate interneuron arborization onto Purkinje cell dendrites

Purkinje cells (shown in yellow) receive synaptic inputs (shown in green) from stellate interneurons (shown in blue) at only the distal portions of their dendrites. Bergmann glia (shown in red) cell processes act as a scaffold for stellate axon guidance and synaptogenesis onto Purkinje cell dendrites. Figure is modified from REF. .

Figure 6. The role of Cajal–Retzius cells and subplate cells in neural circuit formation

a | Cajal–Retzius cells and GABA (γ-aminobutyric acid)-ergic interneurons have roles in establishing layer specificity in the hippocampus. In the vertebrate embryo, pyramidal dendrites (shown in yellow) are found only in the stratum radiatum (SR) layer. Commissural and associational (C and A) axon fibres (shown in light purple) preferentially form synaptic contacts (shown in green) onto GABAergic interneurons (shown in red), which are also found in the SR layer. Axons from the entorhinal cortex (EC) (shown in light blue) form synapses onto Cajal–Retzius cells (shown in dark purple), found in the stratum lacunosum-moleculare (SLM) layer, before the pyramidal dendrites reach the SLM. Dashed lines delineate the SLM and SR layers. In the postnatal vertebrate many Cajal–Retzius cells and GABAergic interneurons are removed through regulated cell death, and pyramidal dendrites extend into the SLM to form synapses on both entorhinal and C and A afferents on distinct dendritic domains. b | Subplate neurons act as transient synaptic targets in the formation of the thalamocortical circuit. Early in development, lateral geniculate nucleus (LGN) axons (shown in red) accumulate in the subplate (SP) and form synaptic connections (shown in green) with subplate neurons (shown in purple). Subplate neurons send axons into the cortical plate and form synaptic connections with layer 4 cortical neurons (shown in blue). Later in development, LGN neurons grow into cortical layer 4 and form synapses onto both subplate and layer 4 neurons. In the adult, subplate neurons are eliminated by regulated cell death and LGN axons form mature synaptic connections on cortical layer 4 neurons. WM, white matter. Data from REF. and REF. .

Figure 7. Non-neuronal cells as guideposts in synaptic specificity

a | AIY–RIA connectivity is determined by ventral cephalic sheath glial cells. In the Caenorhabditis elegans nerve ring neuropil, the interneuron AIY forms synapses onto the interneuron RIA at a specific spatial coordinate (indicated by the box and the black shading). This coordination of synapse formation is mediated by netrins expressed by cephalic sheath glia (shown in yellow), which ensheath the contact area between AIY and RIA. b | The presynaptic location of the neuron HSNL is determined by vulval epithelial guidepost cells. In the C. elegans egg-laying circuit, HSNL forms synapses (shown in green) on VC4 and VC5 neurons and vulval muscles (M). This synaptic pattern is determined by vulval epithelial cells (shown in blue) that express the cell adhesion molecule SYG-2, which localizes its HSNL-expressed receptor, SYG-1. SYG-1 is necessary for synapse formation. c | A diagram of a C. elegans tail with the DA9 neuron (shown in black) and its synaptic pattern (shown as green circles). Wnt-secreting cells and netrin-secreting cells cooperate to prevent synapse formation in the commissural and dendritic region of the DA9 neuron. Wnts act through their receptor, frizzled, and netrin acts through its receptor, UNC-5, to inhibit synapse formation. Data from REF. and REF. .