Abstract
Cell fate is maintained over long timescales, yet molecular fluctuations can lead to spontaneous loss of this differentiated state. Our simulations identified a possible mechanism that explains life-long maintenance of ASE neuron fate in Caenorhabditis elegans by the terminal selector transcription factor CHE-1. Here, fluctuations in CHE-1 level are buffered by the reservoir of CHE-1 bound at its target promoters, which ensures continued che-1 expression by preferentially binding the che-1 promoter. We provide experimental evidence for this mechanism by showing that che-1 expression was resilient to induced transient CHE-1 depletion, while both expression of CHE-1 targets and ASE function were lost. We identified a 130 bp che-1 promoter fragment responsible for this resilience, with deletion of a homeodomain binding site in this fragment causing stochastic loss of ASE identity long after its determination. Because network architectures that support this mechanism are highly conserved in cell differentiation, it may explain stable cell fate maintenance in many systems.
Highlights
In most animal tissues, terminally differentiated cells are renewed on timescales of days to months (Leblond and Walker, 1956), yet the nervous system is unique, as most neurons hardly renew at all (Ming and Song, 2005)
We speculate that homeodomain proteins have a role in maintaining and stabilizing ASE fate, potentially by recruiting che577 1::GFP::AID L1 larvae (CHE-1) preferentially to its own promoter. 112 Results 113 114 Loss of ASE neuron fate upon transient CHE-1 depletion 115 116 To test whether positive autoregulation of che-1 expression is necessary for ASE fate maintenance, we depleted CHE-1 protein levels in ASE neurons in vivo, using the auxin inducible degradation system (Serrano-Saiz et al, 2018; Zhang et al, 2015). che119 1::GFP::Auxin-Induced Degradation (AID) animals were exposed to 1 mM auxin to induce CHE-1::GFP::AID depletion 120 (Figure 1C)
In animals exposed to auxin for 24 hrs, both CHE-1::GFP::AID expression 139 and NaCl chemotaxis returned to wild-type levels after 24 hrs recovery (Figure 1D, Figure 140 1-figure supplement 1B, Figure 1-figure supplement 2C)
Summary
Terminally differentiated cells are renewed on timescales of days to months (Leblond and Walker, 1956), yet the nervous system is unique, as most neurons hardly renew at all (Ming and Song, 2005). These act through a conserved network motif called a single-input module (Alon, 2007): they bind to specific cis-regulatory control elements to induce both their own expression and that of the downstream target genes that define the neuronal type (Figure 1A) Such terminal selector networks have been found to underlie differentiation of several neuron types in the nematode Caenorhabditis elegans (Deneris and Hobert, 2014; Hobert, 2016), photoreceptor subtypes in Drosophila (Hsiao et al, 2013) and dopaminergic neurons in mice (Ninkovic et al, 2010), indicating that they form an evolutionary conserved principle for neuron type determination. The impact of molecular noise, such as variability in CHE-1 protein copy number, on ASE fate maintenance has not been studied Overall, it is an open question how a reversible, bistable switch based on positive CHE-1 autoregulation would remain sufficiently stable for the animal’s lifetime to maintain ASE fate, or if additional mechanisms are necessary to ensure its stability. We speculate that homeodomain proteins have a role in maintaining and stabilizing ASE fate, potentially by recruiting CHE-1 preferentially to its own promoter
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