Abstract
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 neurons through stochastic competition for target-derived neurotrophic signals, implying an equal potential for neurons to compete. Here we show an alternative cell fitness selection of neurons that is defined by a specific neuronal heterogeneity code. Proprioceptive sensory neurons that 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 neurons with contrasted functional maturation states and survival outcome. Thus, in this model, a heterogeneous code of intrinsic cell fitness in neighboring neurons provides differential competitive advantage resulting in the selection of cells with higher capacity to survive and functionally integrate into neural networks.
Highlights
Developmental cell death plays an important role in the construction of functional neural circuits
In the peripheral nervous system, survival of selected neurons depends on targetderived neurotrophins (NTs)[5,6], which bind to specific tropomyosin receptor kinase (TRK) receptors on the neuronal cell surface[7]
We show that before cell death period starts, the presumptive proprioceptive sensory neurons (PSNs) display different molecular blueprints initiated by the morphogen retinoic acid (RA) and which lead through transcriptional regulation to distinct subgroups of neurons with different functional fitness and survival outcome
Summary
Developmental cell death plays an important role in the construction of functional neural circuits. Very early on, neurons exhibit intrinsic differences that control their differentiation and axon targeting[15,16,17], emphasizing the need to re-examine the stochastic nature of the neurotrophic theory and to determine whether cell-to-cell molecular variability and survival predictability represent strong selection mechanisms during neuronal competition for NTs-induced survival (Fig. 1a). In this context, a more deterministic life-or-death regulation, coupled with these intrinsic differentiation mechanisms, would provide a way for selecting the fittest cells during development. Our data demonstrate a predisposition to cell death during development, where molecular fitness heterogeneity in sensory neurons predicts their survival probability and the selection of the fittest cells for the establishment of functional neural networks
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