A cell fitness selection model for neuronal survival during development

Developmental cell death plays an important role in the construction of functional neural circuits. In vertebrates, the canonical view proposes a selection of the surviving neuronsthrough stochastic competition for target-derived neurotrophic signals, implying an equal potential for neuronsto compete. Here we show an alternative cell fitness selection of neuronsthat is defined by a specific neuronalheterogeneity code. Proprioceptive sensory neuronsthat will undergo cell death and those that will survive exhibit different molecular signatures that are regulated by retinoic acid and transcription factors, and are independent of the target and neurotrophins. These molecular features are genetically encoded, representing two distinct subgroups of neuronswith contrasted functional maturation states and survival outcome. Thus, in this model, a heterogeneous code of intrinsic cell fitness in neighboring neuronsprovides differential competitive advantage resulting in the selection of cells with higher capacity to survive and functionally integrateinto neural networks. Programmed cell death is an important part of tissue development, and traditionally it is considered that neuronaldeath is a stochastic process in response to neurotrophic factor deprivation. Here the authors show that for TrkC+ proprioreceptors, which neuronsdie is predetermined molecularly by how much TrkC is present, as well as by a gene expression signature.