Abstract
In terrestrial vertebrates such as birds and mammals, neurotrophin receptor expression is considered fundamental for the specification of distinct somatosensory neuron types where TrkA, TrkB and TrkC specify nociceptors, mechanoceptors and proprioceptors/mechanoceptors, respectively. In turn, Runx transcription factors promote neuronal fate specification by regulating neurotrophin receptor and sensory receptor expression where Runx1 mediates TrkA+ nociceptor diversification while Runx3 promotes a TrkC+ proprioceptive/mechanoceptive fate. Here, we report in zebrafish larvae that orthologs of the neurotrophin receptors in contrast to terrestrial vertebrates mark overlapping and distinct subsets of nociceptors suggesting that TrkA, TrkB and TrkC do not intrinsically promote nociceptor, mechanoceptor and proprioceptor/mechanoceptor neuronal fates, respectively. While we find that zebrafish Runx3 regulates nociceptors in contrast to terrestrial vertebrates, it shares a conserved regulatory mechanism found in terrestrial vertebrate proprioceptors/mechanoceptors in which it promotes TrkC expression and suppresses TrkB expression. We find that Cbfβ, which enhances Runx protein stability and affinity for DNA, serves as an obligate cofactor for Runx in neuronal fate determination. High levels of Runx can compensate for the loss of Cbfβ, indicating that in this context Cbfβ serves solely as a signal amplifier of Runx activity. Our data suggests an alteration/expansion of the neurotrophin receptor code of sensory neurons between larval teleost fish and terrestrial vertebrates, while the essential roles of Runx/Cbfβ in sensory neuron cell fate determination while also expanded are conserved.
Highlights
Sensory neurons of the dorsal root ganglia (DRG) and trigeminal ganglia (TG) of terrestrial vertebrates convey somatosensory information from the body and face, respectively
In our study we show that mechanisms by which Runx transcription factors regulate neurotrophin receptor expression are conserved between zebrafish and terrestrial vertebrates, yet the type of neuron specified by these genes are different such that in zebrafish the neurotrophin receptor TrkC is expressed in a nociceptor lineage instead of the proprioceptor/mechanoreceptor lineage as in terrestrial vertebrates
We show in fish that zebrafish Runx3 has properties that are divided between Runx1 and Runx3 in terrestrial vertebrates
Summary
Our perception of the external world comes from our senses. Often overlooked the skin is our largest sensory organ. (DRG), which innervate the body, and trigeminal ganglion (TG), which innervate the face, sense the somatosensory perceptions: light touch, temperature, pain (nociceptors) and muscle/limb position (proprioception) via nerve endings that project to the skin. These neurons receive and relay information from these diverse stimuli through distinct subclasses of neurons. In our study we show that mechanisms by which Runx transcription factors regulate neurotrophin receptor expression are conserved between zebrafish and terrestrial vertebrates, yet the type of neuron specified by these genes are different such that in zebrafish the neurotrophin receptor TrkC is expressed in a nociceptor lineage instead of the proprioceptor/mechanoreceptor lineage as in terrestrial vertebrates These data demonstrate that the specification of neuronal lineages is not fundamental to a given neurotrophin receptor but has adapted and evolved from the time fish and terrestrial vertebrates diverged 350 million years ago. We show that the Runx co-factor Cbfβ is essential for its function, but the high level of Runx expression can overcome the loss of Cbfβ, demonstrating that Cbfβ in this context serves solely as a signal amplifier of Runx activity
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