Repression of an activity-dependent autocrine insulin signal is required for sensory neuron development inC. elegans

Abstract

24Nervous system development is instructed both by genetic programs and activity-dependent 25 refinement of gene expression and connectivity. How these mechanisms are integrated remains 26 poorly understood. Here, we report that the regulated release of insulin-like peptides (ILPs) 27 during development of the C. elegans nervous system accomplishes such an integration. We 28 find that the p38 MAP kinase PMK-3, which is required for the differentiation of chemosensory 29 BAG neurons, functions by limiting expression of an autocrine ILP signal that represses a 30 chemosensory-neuron fate. ILPs are released from BAGs in an activity-dependent manner 31 during embryonic development, and regulate neurodifferentiation through a non-canonical 32 insulin receptor signaling pathway. The differentiation of a specialized neuron-type is, therefore, 33 coordinately regulated by a genetic program that controls ILP expression and by neural activity, 34 which regulates ILP release. Autocrine signals of this kind may have general and conserved 35 functions as integrators of deterministic genetic programs with activity-dependent mechanisms 36 during neurodevelopment. 37 38 2017). How these two different mechanisms -one specified and the other activity-dependent -47 are integrated during nervous system development remains poorly understood. 48The C. elegans nervous system displays a wide range of neuronal diversity, and is a 49 powerful model to study neuronal differentiation (White et al. 1986;Hobert et al. 2016). The 50 mostly invariant cell lineage that generates the C. elegans nervous system (Sulston 1977; 51 Sulston 1983) suggests that neuronal differentiation in C. elegans is principally determined by 52 genetic programs intrinsic to the cell-lineage. Indeed, many studies have identified transcription 53 factors that act in specific sub-lineages to promote specific neural fates (Hobert 2016). However, 54there are also important roles for neuronal activity during development of the C. elegans nervous 55 system. For example, there is a striking role for activity of embryonic AWC chemosensory 56 neurons in determining their differentiation into functionally distinct subtypes (Troemel 1999; 57 Sagasti 2001). More recently, it has been found that there is a critical period during which neural 58 activity instructs circuit assembly in the C. elegans motor system (Barbagallo et al. 2017). Post-59 developmentally, neural and sensory activity is required for maintaining the proper morphology 60 of chemosensory neurons (Peckol 1999; Mukhopadhyay et al. 2008), and for expression of 61 chemosensory receptors and neuropeptides that define specific chemosensory neuron fates 62 (Peckol et al. 2001; Gruner et al. 2014; Rojo Romanos et al. 2017). Like the vertebrate nervous 63 system, therefore, development of the C. elegans nervous system requires both lineally 64 programmed gene regulation and neural activity. 65 We have investigated mechanisms required for the development of a pair of C. elegans 66 sensory neurons -the BAGs, which se...

The neuropeptidergic connectome ofC. elegans

“…Autocrine peptide signaling is ubiquitous in other brains as well 97,98 , suggesting it supports important aspects of neural function. For example, autocrine neuropeptide pathways are known to mediate cell-autonomous feedback [99][100][101][102][103][104] , and are therefore often suggested to maintain neuronal homeostasis; this may be particularly important to regulate the activity of tonically signaling neurons, such as the oxygen-sensing neurons. In the motor circuit, ostensibly autocrine signaling may play a further role by coordinating the activities of neighboring neurons with similar gene expression patterns.…”

Gut neuroendocrine signaling regulates synaptic assembly in C. elegans

“…The invertebrate neural circuits were initially thought to be genetically hardwired (Jin et al , 1999; Gally & Bessereau, 2003; Hiesinger et al , 2006; Klassen & Shen, 2007), although neural activity can regulate the remodeling or plasticity (Zhao & Nonet, 2000; Sachse et al , 2007; Tessier & Broadie, 2009; Thompson‐Peer et al , 2012; Hart & Hobert, 2018; Cuentas‐Condori et al , 2019). However, recent studies have shown that neuronal activity during embryogenesis regulates neuronal differentiation (Horowitz et al , 2019), presynaptic subcellular specificity (Wang et al , 2021) in C. elegans , indicating the important role of experience‐independent activity in circuit development. In vertebrates, it is well known that neural activity regulates synaptic formation and plasticity (Hooks & Chen, 2020; Pan & Monje, 2020).…”