Brain wiring with composite instructions

Abstract

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.

Systematic functional analysis of rab GTPases reveals limits of neuronal robustness to environmental challenges in flies

“…Our mutant analyses highlight that viability vs lethality is not a binary distinction of the null mutants, but represents a continuous range of context-dependent phenotypes ( Hiesinger, 2021 ). Of the 26 null mutants, only seven are fully lethal under laboratory conditions in our study ( rab1 , rab2 , rab5 , rab6 , rab7 , rab8 , rab11 ), while an eighth mutant is 'semi-lethal' based on few adult escapers ( rab35 ).…”

Variable brain wiring through scalable and relative synapse formation inDrosophila

“…However, such a molecular ‘hierarchy of preference’ would have to include at least all the non-canonical synapses shown in this study for yR7 neurons and DCNs. To what extent molecular interactions play earlier developmental roles prior to synapse formation ( 63 ) and to what extent synapse formation could be promiscuous based on specification through proximity and kinetics ( 6 ) remains a matter of debate ( 10, 11, 64 ).…”

“…Since both the number and the specificity of partnerships of yR7 synapses in the DIPγ mutant scale with developmental temperatures similar to wild type, we propose that synaptic specificity is a developmental outcome of a composite of relative contributors that include spatiotemporal availability, interaction kinetics, as well as interaction biases through molecular recognition between partner cells ( 64 ). In this view, the removal or alteration of a single relative contributor, e.g.…”

Brain connectivity inversely scales with developmental temperature in Drosophila

“…As both the number and the specificity of partnerships of yR7 synapses in the DIPg mutant scale with developmental temperatures similar to wild-type, we propose that synaptic specificity is a developmental outcome of a composite of relative contributors that include spatiotemporal availability, interaction kinetics, and interaction biases through molecular recognition between partner cells (Hiesinger, 2021). In this view, the removal or alteration of a single relative contributor (e.g., the spatiotemporal availability of the main postsynaptic partner cell) increases the relative contribution of other factors, including the availability of other cells and their likelihood to form synapses on the basis of interaction kinetics (Agi et al, 2020;Kiral et al, 2020).…”

“…However, such a molecular ''hierarchy of preference'' would have to include at least all the non-canonical synapses shown in this study for yR7 neurons and DCNs. To what extent molecular interactions play earlier developmental roles prior to synapse formation (Petrovic and Schmucker, 2015) and to what extent synapse formation could be promiscuous on the basis of specification through proximity and kinetics (Agi et al, 2020) remain a matter of debate (Hassan and Hiesinger, 2015;Hiesinger, 2021;Sanes and Zipursky, 2020).…”