Neuronal Polarity and the Epithelial Metaphor

The concept that the neuron lies wholly within the basolateral compartment (Figure 4Figure 4) may also be deduced from an analysis of the plasma membrane specializations that are assembled on its surface. The neuron does not make tight junctions, consistent with the argument that it cannot segregate off an apical domain for itself; neither does the neuron make desmosomes (Peters et al. 1991xPeters, A.A, Palay, S.L, and Webster, H.D. See all ReferencesPeters et al. 1991), possibly because it is not subject to mechanical stresses. However, adherens junctions abound on the neuronal surface; these junctions connect it to other neurons, and it is at these adherens junctions that the physiological synapse is found. The argument has been presented that the adherens junction is the evolutionary antecedent of the chemical synapse (3xFannon, A.M and Colman, D.R. Neuron. 1996; 17: 423–434Abstract | Full Text | Full Text PDF | PubMed | Scopus (338)See all References, 11xShapiro, L and Colman, D.R. Neuron. 1999; 23: 427–430Abstract | Full Text | Full Text PDF | PubMed | Scopus (164)See all References). In brief, the evidence for this is that the epithelial adherens junction and the CNS synaptic junctional complex are morphologically similar adhesive and signaling devices consisting of plasma membrane thickenings with underlying electron-dense material. There is a narrow, remarkably uniform cleft between plasma membranes of ∼150–300 A. The junctional membranes are invariantly in register, parallel to one another, and cannot be separated from one another by physical means. Most telling, it has recently become clear that the adherens junction and the CNS synapse share identical adhesive elements, in that both are at least in part cadherin mediated structures, containing not only these calcium-dependent adhesion molecules but cadherin-associated proteins as well (Uchida et al. 1996xUchida, N, Honjo, Y, Johnson, K.R, Wheelock, M.J, and Takeichi, M. J. Cell Biol. 1996; 135: 767–779Crossref | PubMed | Scopus (386)See all ReferencesUchida et al. 1996).Figure 4The Synaptic Junctional Complex in the CNS, an Adherens Junction Derivative, Is Found All Over the Neuronal SurfaceConceptually, neurons in situ abut the basolateral domain of an epithelium and therefore express only the features of that domain on their surface. The synaptic junctional complex in the CNS is essentially an epithelial adherens junction, a specialization of the lateral domain that is further specialized by neurons for highly sophisticated cell–cell communication.View Large Image | View Hi-Res Image | Download PowerPoint SlideOne might argue that there are problems inherent in the foregoing analysis. In particular, in epithelia, adherens junctions connect each cell in its layer to its immediately adjacent, laterally positioned neighbors, and not to distant cells in “other” layers. This “somacentric” view of simple epithelial attachments must however be broadened when considering CNS architecture. In the CNS, axons and dendrites interconnect in a staggeringly complex three-dimensional neuropil; where are the laterally connected cellular layers? Although cell body layers are of course apparent in the mature CNS—in cortical structure, for example—more importantly, dendritic and axonal plasma membrane domains are frequently organized in clearly recognizable layers or lamina (as in retina, optic tectum, and hippocampus). In the CNS, physiologically coupled neurons are physically interconnected via adherens (synaptic) junctions placed along axons and dendrites that have evolved to operate at substantial distances from the cell body. Thus, in the CNS epithelium, physical connection and consequent neuronal activity may be thought of as “action at a distance.” But essentially the same adherens junction that links adjacent simple epithelial cells also links neurons via their axonal and dendritic extensions.In summary, by relegating the apical domain in the brain to its proper and only surface—the ependymal lining facing the ventricular lumen—and thereby completely dissociating it from axonal polarity, we are conceptually positioned to reframe the question of how neurons sort and target proteins. In essence, we free up the axon from the constraints of an “apical” designation and consider it purely as a greatly elongated Golgi apparatus-to-plasma membrane compartment (the absence of ribosomal subunits in axons in Chordata is one strong argument for this last contention). We should develop, I think, a different framework upon which to evaluate the full complement of mechanisms that act to polarize so many types of neuronal cell surfaces in three-dimensional space.Some of the fundamental subcellular mechanisms that organize the plasma membranes of uniform, simple epithelia are of course utilized also by neurons. However, these mechanisms—and the experiments reviewed by Winckler and Mellman 1999xWinckler, B and Mellman, I. Neuron. 1999; 23: 637–640Abstract | Full Text | Full Text PDF | PubMed | Scopus (111)See all ReferencesWinckler and Mellman 1999 clearly reveal this—are insufficient to account for the complex polarity observed in the numerous neural cell phenotypes. Neurons have greatly expanded upon the basic mechanism repertoire and have evolved novel and highly sophisticated strategies to differentially distribute, with exquisite and absolute precision, the intracellular protein traffic, such that within even “simple” dendritic and axonal arborizations, multiple plasma membrane subdomains may be discerned (1xCraven, S.E, El-Husseini, A.E, and Bredt, D. Neuron. 1999; 22: 497–509Abstract | Full Text | Full Text PDF | PubMedSee all References, 10xSerafini, T. Cell. 1999; 98: 133–136Abstract | Full Text | Full Text PDF | PubMed | Scopus (59)See all References, 15xWinckler, B, Forscher, P, and Mellman, I. Nature. 1999; 397: 698–701Crossref | PubMed | Scopus (263)See all References).*To whom correspondence should be addressed (e-mail: colman@msvax.mssm.edu).