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Maintenance of neurotransmitter identity by Hox proteins through a homeostatic mechanism

Weidong Feng, Honorine Destain, Jayson J Smith, Paschalis Kratsios

Preprint posted on 5 May 2022 https://www.biorxiv.org/content/10.1101/2022.05.05.490791v1

Article now published in Nature Communications at http://dx.doi.org/10.1038/s41467-022-33781-0

Hox has got the nerves. Hox genes maintain neurotransmitter identity from development to adulthood.

Selected by Chee Kiang Ewe

Background:

The Hox genes encode evolutionarily conserved transcription factors that are crucial for the development of the body plan along the anterior-posterior axis of animals (Pearson et al., 2005). Additionally, Hox proteins are known to modulate early specification of the nervous system (Parker & Krumlauf, 2020). However, whether Hox proteins also control the subsequent differentiation of neurotransmitter identity of neurons is unclear.

C. elegans contains six Hox genes: ceh-13, lin-39, mab-5, egl-5, nob-1, and php-3, many of which are required for neuronal fate specification during early development. In this preprint, the authors used motor neurons of the C. elegans ventral nerve cord to investigate whether Hox may regulate neurotransmitter identity after embryogenesis. They found that LIN-39 and MAB-5, together with UNC-3 (ortholog of Collier/Olf/EBF transcription factor), control cholinergic identity of motor neurons throughout the life of the worm by modulating the expression of genes acting in the acetylcholine (ACh) pathway. This study provides an important insight into the roles of Hox proteins in neuronal cell fate regulation in postembryonic animals.

Major findings:

  1. Hox proteins and UNC-3 maintain cholinergic identity of motor neurons

The authors found that LIN-39 and MAB-5 were expressed in many motor neurons. Depleting LIN-39 using the auxin-inducible system (and therefore bypassing the early roles of LIN-39) reduced the number of neurons expressing terminal cholinergic markers (unc-17, ace-2, and cho-1). Knocking out mab-5 in the absence of lin-39 further enhanced this defect, suggesting that LIN-39 and MAB-5 function synergistically to control the fate of cholinergic motor neurons.

UNC-3 was previously found to play an important role in activating and maintaining cholinergic gene expression (Kratsios et al., 2011). Indeed, triple mutant animals missing lin-39, mab-5, and unc-3 exhibited a severe loss of motors neuron expressing ACh pathway genes. By examining publicly available ChIP-Seq data, the authors showed that cho-1, unc-17, and ace-2 were the direct targets of LIN-39, MAB-5, and UNC-3.

  1. The gene regulatory logic underlying the maintenance of cholinergic identity

The authors found that LIN-39 and MAB-5 bound to and activated the expression of unc-3. Indeed, the expression of unc-3 was downregulated in mutants lacking lin-39 alone or both lin-39 and mab-5 (Figure 1). This feedforward regulatory logic was proposed to be important for the robustness of cell fate maintenance. Interestingly, the authors found that LIN-39 might activate its own expression by binding to the regulatory sites in the intron. Mutating LIN-39 binding sites in its first intron strongly reduced its expression levels. Similarly, MAB-5 may maintain its expression via autoregulation. The authors further showed that lin-39 and mab-5 were upregulated when unc-3 was absent, suggesting cross-regulation of the transcription factors maintains optimal levels of Hox gene expression (Figure 1).

Gene regulatory circuit for the control of cholinergic identity by Hox (LIN-39 and MAB-5) and UNC-3

Figure 1: Gene regulatory circuit for the control of cholinergic identity by Hox (LIN-39 and MAB-5) and UNC-3 (adapted from Figure 7, Feng W. et al., 2022).

What I liked about this preprint:

By using the powerful auxin-inducible system to deplete Hox protein in post-embryonic animals, the authors uncovered the novel roles of Hox proteins as terminal differentiation factors, as well as the gene regulatory circuit that underlies the maintenance of neurotransmitter identity. It will be very interesting to investigate whether the roles of Hox proteins in neuronal cell fate maintenance is evolutionary conversed in vertebrates.

Questions for the authors:

Have you examined the fate of the motor neurons that have lost unc-17/ace-2/cho-1 expression in lin-39(-); mab-5(-)? Do they adopt an alternate neurotransmitter identity?

What happens when mab-5 or lin-39 is overexpressed in the motor neurons?

References:

Kratsios, P., Stolfi, A., Levine, M., & Hobert, O. (2011). Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene. Nature Neuroscience 2011 15:2, 15(2), 205–214. https://doi.org/10.1038/nn.2989

Parker, H. J., & Krumlauf, R. (2020). A Hox gene regulatory network for hindbrain segmentation. Current Topics in Developmental Biology, 139, 169–203. https://doi.org/10.1016/BS.CTDB.2020.03.001

Pearson, J. C., Lemons, D., & McGinnis, W. (2005). Modulating Hox gene functions during animal body patterning. Nature Reviews Genetics 2005 6:12, 6(12), 893–904. https://doi.org/10.1038/nrg1726

 

Tags: cell fate, cholinergic neuron, gene regulation, hox

Posted on: 16 May 2022

doi: https://doi.org/10.1242/prelights.32017

Read preprint (No Ratings Yet)

Author's response

Paschalis Kratsios shared

Have you examined the fate of the motor neurons that have lost unc-17/ace-2/cho-1 expression in lin-39(-); mab-5(-)? Do they adopt an alternate neurotransmitter identity?

We actually do not know if loss of Hox results in gain of a new neurotransmitter identity. Great suggestion.

What happens when mab-5 or lin-39 is overexpressed in the motor neurons?

When we overexpress LIN-39 in cholinergic motor neurons, they partially adopt a mixed identity. That is, they retain their cholinergic identity but gain molecular markers of other GABAergic neurons. We never overexpressed mab-5, but we should.

1 comment

1 month

Chee Kiang (Ethan) Ewe

This work has identified the gene regulatory network underlying the maintenance of neurotransmitter identity in C. elegans. The preprint was very well written and the major conclusions were well supported by the genetic data. In the published version of the article, the authors further probed the functional significance of the gene network and showed that disrupting autoregulation of lin-39 reduces the expression cho-1. In addition, the authors showed that disrupting Hox binding sites on unc-3 leads to the upregulation of cholinergic identity genes, strengthening the conclusion that the gene network acts to fine tune gene expression important for cellular identity. Besides this, I did not spot any major changes between the preprint and the published article. Congratulations, Feng et al., on publishing this important work!

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