The role of cell-surface diversity in the building a neural circuit

During brain development, the assembly of functional neural circuits requires mechanisms to connect different neurons. Crucial to this process is the ability of neurites (axons and dendrites) of individual neurons to distinguish between themselves and neurites from other neurons. This mechanism is known as self-avoidance and requires that, in principle, every neuron must express a unique combination of cell-surface recognition molecules to generate a molecular recognition code, i.e. an identity. The long-term goal of our laboratory is to dissect the molecular mechanisms behind the generation of such code in mammals.

Clustered Protocadherins genes: a code for neural cell-surface diversity

In mammals, the generation of a cell-surface diversity code for neural self-avoidance requires stochastic and combinatorial expression of only a small subset of clustered Protocadherin (Pcdh) genes, randomly chosen from a total of 60. This is a remarkable task especially given that these 60 nearly-identical genes are organized in tandem and are sequestered within a chromatin state, doubly locked by DNA and H3K9 methylation and thus generally refractive to transcription. At the core of such elegant mechanism for the generation of protein isoform diversity,  two fundamental questions still remained unanswered:

• How is random choice of a small number of nearly identical genes achieved?
• How does localized expression occur in a repressive environment? 

We use genomic, genetics, biochemical and biophysical approaches to dissect the exquisite coupling between 3D chromosome architecture, the underlying chromatin structure, transcription and RNA processing that enables the generation of such enormous diversity of molecular identities in neurons.