Research offers new insights in how our brains are wired

11 December 2015
​The complexity of brain wiring is one of the biggest mysteries in biology. The Dietmar Schmucker Lab (VIB/KU Leuven) investigates the molecular mechanisms that control the growth and branching of neurons. Understanding this process could be essential in treating neurological diseases or devise better strategies for nerve regeneration in response to injuries. In a recent study, published in ‘Cell’, they provide new insights in the way neurons control the formation of stereotyped axon collaterals. We asked Dietmar to elaborate.

Why is the growth of neurons such an interesting research field?
The human brain contains billions of neurons, which are interconnected by axons and dendrites. While many of the factors guiding primary axon processes have been identified, it is still unclear how axons can form collateral branches and how these collaterals choose distinct paths and targets.

How does your recent paper fit into earlier findings?
In the past few years, we have studied axonal branching using systematic genetic screens and by dissecting the function of the membrane receptor Dscam1 in fruit flies. Dscam1 protein is specifically expressed on the surface of growing axons and dendrites. Neurons can create approximately 18,500 slightly different isoforms of Dscam1, which serve as ‘identity tags’ on nerve processes. In principal, even just a reduction of Dscam1 isoform diversity can lead to a striking reduction of axon branching. In the most recent study, graduate students Dan Dascenco, Malu Erfurth, and co-workers have provided new insights in the developmental mechanisms controlling the specificity of axon collateral formation.

What does the research show exactly?
Let me explain by giving an example. Let’s say Neuron X forms a single axon that splits up into three distinct branches. Branch 1 connects with target A, branch 2 with target B, and branch 3 with target C. We are trying to identify mechanisms that assure that always exactly three branches are formed in neuron X and that each of the targets is innervated equally. Moreover, we are trying to identify factors that tell branch 2 to connect with target B and not target A.” “The research shows that disrupting the interplay of proteins Dscam1, the receptor Tyrosine Phosphatase 69D (RPTP69D), and the extracellular ligand Slit, can lead to defects such that branch 2 is not formed at all or it does not connect with target B. Using genetics, cell culture and biochemistry, the lab has worked out a novel molecular pathway by which the spatially restricted and limiting signal Slit binds directly to Dscam1, thereby enhancing complex formation with RPTP69D and the dephosphorylation of the Dscam1 cytoplasmic domain. Overall, the results highlight the importance of a precise, localized regulation of Dscam1 signalling by phosphorylation/dephosphorylation of its cytoplasmic domain.

What is the significance of these findings?
Extensive knowledge of the mechanisms used by neurons to control the specificity of axonal growth and branching will be essential in understanding neurological diseases such as mental retardation or
autism spectrum disorders. It may shed new light on what goes wrong when neurological disorders
arise. It may also give us important insights of how to stimulate and activate nerve regeneration in order to recover from nerve injury. This understanding is also important for guiding future therapies that utilize stem cells as treatment for certain neurological disorders and require the “rebuilding” of damaged neuronal connections.

Dascenco et al., Cell. 2015

Dietmar Schmuker