Harvard University - Department of Molecular & Cellular Biology

IT'S NOT YOU, IT'S ME [SANES LAB]

by Joshua Sanes

July 30th, 2012

(L to R) Dimitar Kostadinov, Joshua Sanes, and Julie Lefebvre

Neurons in the brain extend elaborately branched dendrites that receive inputs from other neurons and sensory stimuli.  In some cases, the dendrites exhibit a behavior called self-avoidance, in which individual branches keep to themselves, seemingly repelling each other.  Self-avoidance serves to minimize gaps and overlaps in a neuron’s arbor, thereby allowing it to maximize the number of inputs it receives.  However, self-avoidance comes with a price:  dendrites of some neurons need to form synaptic connections with dendrites of other neurons of the same type.  These dendrites need to solve the difficult problem of “self/non-self discrimination,” avoiding other dendrites from the same cell while connecting with dendrites of other, seemingly identical cells. In a paper in Nature, Lefebvre et al. show that part of the secret lies in a complex set of 22 genes called gamma-protocadherins.  Using several lines of genetically engineered mice, they show that self-avoidance fails in particular cell types of the retina and cerebellum when the gamma-protocadherins are absent.  Dendrites grow normally, but fail to repel each other and thus clump up. But if all cells have gamma-protocadherins, why do dendrites of neighboring cells not avoid each other?  Lefebvre et al. hypothesized that each cell bears only a few of the gamma-protocadherins, chosen at random from the full set of 22, and that dendrites only repel when they bear the same subset.   Normally, the only time a dendrite would encounter a perfect match is in another dendrite of the same cell.  Lefebvre et al. realized they could test this idea by expressing the same gamma-protocadherin in all neurons of a particular type and asking whether dendrites were now unable to distinguish self from non-self, and ended up avoiding neighboring cells.  In fact, that is exactly what they saw, supporting the idea that protocadherins can help give each neuron within a group a unique molecular identity.

Matters are still more complicated, though –the gamma-protocadherins are required for survival of some cells as well as self-avoidance in others.  Lefebvre et al. collaborated with Weisheng Chen and Tom Maniatis, formerly in MCB and now at Columbia, to disentangle these two functions.  In another surprising twist, it turns out that any gamma-protocadherin can function in self-avoidance but only a few promote survival.  Some of the results of this collaborative study are presented in the paper by Lefebvre et al., and others in a paper by Chen et al., appearing simultaneously in Neuron.  How these remarkable genes manage to perform these two very different tasks is the subject of ongoing work between the two groups.

Read the paper in Nature: Protocadherins mediate dendritic self-avoidance in the mammalian nervous system

Read the related paper in Neuron: Functional Significance of Isoform Diversification in the Protocadherin Gamma Gene Cluster (PDF file)

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