Brain wiring with composite instructions

The quest for molecular mechanisms that guide axons or specify synaptic contacts has largely focused on molecules that intuitively relate to the idea of an “instruction.” By contrast, “permissive” factors are traditionally considered background machinery without contribution to the information content of a molecularly executed instruction. In this essay, I recast this dichotomy as a continuum from permissive to instructive actions of single factors that provide relative contributions to a necessarily collaborative effort. Individual molecules or other factors do not constitute absolute instructions by themselves; they provide necessary context for each other, thereby creating a composite that defines the overall instruction. The idea of composite instructions leads to two main conclusions: first, a composite of many seemingly permissive factors can define a specific instruction even in the absence of a single dominant contributor; second, individual factors are not necessarily related intuitively to the overall instruction or phenotypic outcome.