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Link to original content: http://pubmed.ncbi.nlm.nih.gov/39167071/
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Review
. 2024 Oct 7;228(2):iyae116.
doi: 10.1093/genetics/iyae116.

Neurogenesis in Caenorhabditis elegans

Richard J Poole  1 , Nuria Flames  2 , Luisa Cochella  3
Affiliations
Review

Neurogenesis in Caenorhabditis elegans

Richard J Poole et al. Genetics. .

Abstract

Animals rely on their nervous systems to process sensory inputs, integrate these with internal signals, and produce behavioral outputs. This is enabled by the highly specialized morphologies and functions of neurons. Neuronal cells share multiple structural and physiological features, but they also come in a large diversity of types or classes that give the nervous system its broad range of functions and plasticity. This diversity, first recognized over a century ago, spurred classification efforts based on morphology, function, and molecular criteria. Caenorhabditis elegans, with its precisely mapped nervous system at the anatomical level, an extensive molecular description of most of its neurons, and its genetic amenability, has been a prime model for understanding how neurons develop and diversify at a mechanistic level. Here, we review the gene regulatory mechanisms driving neurogenesis and the diversification of neuron classes and subclasses in C. elegans. We discuss our current understanding of the specification of neuronal progenitors and their differentiation in terms of the transcription factors involved and ensuing changes in gene expression and chromatin landscape. The central theme that has emerged is that the identity of a neuron is defined by modules of gene batteries that are under control of parallel yet interconnected regulatory mechanisms. We focus on how, to achieve these terminal identities, cells integrate information along their developmental lineages. Moreover, we discuss how neurons are diversified postembryonically in a time-, genetic sex-, and activity-dependent manner. Finally, we discuss how the understanding of neuronal development can provide insights into the evolution of neuronal diversity.

Keywords: Caenorhabditis elegans; WormBook; gene regulation; neurodevelopment; neurogenesis; transcription factors.

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Conflict of interest statement

Conflicts of interest The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Regulatory framework for C. elegans neurogenesis. Summary of the main regulatory interactions controlling neurogenesis and neuron diversification that should serve as a roadmap for this chapter. Development of each neuron class requires integration of regulatory information from different developmental timepoints into parallel, yet interconnected regulatory modules that coexist in the cell. (1) Lineage history determines the set of TFs expressed in the neuron and its progenitors, the signalling events it receives over time, and the particular chromatin landscape of the postmitotic neuron (see Lineage-based mechanisms of neuronal diversification). (2) bHLH proneural factors have evolutionary conserved roles in the specification of neuronal progenitors (see Diverse functions of bHLH proneural TFs). (3) Terminal selector TFs act in the postmitotic neuron to directly activate broad neuron class effector gene batteries (see Rich sets of effector genes distinguish different neuron classes and Principles of neuron class specification by terminal selectors). (4) Terminal selectors act together with HOX TFs to diversify some neuron subclasses along the A–P axis (see Neuronal diversification across body axes). (5) Neuron class transcriptomes are also shaped by postembryonic time or genetic sex (see Neuronal diversification over developmental time and across sexes). (6) Mature neurons can modify their transcriptome in response to environmental stimuli (see Environmental effects on neuron gene expression). (7 and 8) At least 2 regulatory modules run in parallel to those specifying neuron class properties: panneuronal effector genes, those shared by all neuron classes are under direct control of CUT HD TFs (7) (see Panneuronal features define neurons as a tissue type) while different TFs activate the ciliome components expressed by all sensory ciliated neurons (8) (see Rich sets of effector genes distinguish different neuron classes). t.g., neuron type effector gene; p.g., panneuronal effector gene; c.g., ciliome effector gene.
Fig. 2.
Fig. 2.
Developmental origin of neurons and neuronal diversity. a) Matrix of the 118 morphologically different neuron classes in hermaphrodite C. elegans classified according to different criteria including embryonic/postembryonic lineage, function, and neurotransmitter identity. For simplicity, large effector gene categories, such as neuropeptides or innexins, have not been included but references to their expression patterns are provided in the text. b) Lineage origins of all 302 embryonically and postembryonically generated hermaphrodite neurons. c) A cartoon illustration of a generic neuron depicting different sets of proteins required for specific neuronal functions, which include panneuronal factors such as synaptic components, cilium proteins (ciliome) present in ciliated sensory neurons, and different sets of neuron class-specific effector proteins such as adhesion molecules, enzymes, ion channels, receptors, or neuropeptides.
Fig. 3.
Fig. 3.
Progressive determination model of neuronal development. A cartoon illustration of the progressive determination model of neural development. Key steps relevant to C. elegans include the specification of neural progenitors and the differentiation of postmitotic cells into neurons.
Fig. 4.
Fig. 4.
Expression of bHLH TFs in neuronal lineages. a) Summary of proneural gene expression at any point in the lineage of the indicated embryonic neurons (sources: WormAtlas, Sulston and Horvitz 1977; Sulston et al. 1983; Reilly et al. 2022; Masoudi et al. 2023). b) An illustrative example of sequential bHLH expression in the ABalpp/ABpraa lineage. hlh-3 is expressed both early and broadly and has no known role in this lineage. hlh-14 is expressed in a more restricted manner and is required for neural precursor specification. hlh-4 is only expressed in the ADL neurons where it acts as a terminal selector and not as proneural gene. See the main text for more details.
Fig. 5.
Fig. 5.
Terminal selector functions in neuronal diversification. a) Example of the accumulation of regulatory factors along a lineage to result in specific (and robust) patterns of gene expression (from Walton et al. 2015). b) Terminal selector TFs act combinatorially on modular cis-regulatory sequences, enabling cell-specific control of various terminal effector genes. The modular architecture of cis-regulatory elements enables integration of distinct combinations of terminal selectors, as well as integration with other transcriptional inputs as discussed in the rest of the chapter. The 3 illustrated examples correspond to those described in the text. c) The output of a terminal selector (e.g. UNC-86) can be diversified by integration into gene regulatory networks with other transcriptional regulators. These can be organized in regulatory motifs such as coherent feedforward loops (in which a terminal selector activates an effector gene as well as an additional transcriptional activator, blue arrows) and incoherent feedforward loops (in which a terminal selector activates an effector gene as well as a repressor of the same target gene, red arrows). Such motifs are recurrently used to modify the terminal battery activated by a terminal selector. d) Regulation of the different components of the neuronal transcriptome is achieved thanks to combinatorial TF action on modular cis-regulatory sequences that result in parallel modules that are interconnected. For example, panneuronal gene expression relies on CUT TFs but also receives terminal selector input. Gene modules such as those coding for the structural cilium components are under control of a parallel program driven by FKH-8 and DAF-19C, but other neuron class-specific components of the cilia, just like other neuron-type effector genes, are under terminal selector control.
Fig. 6.
Fig. 6.
Generation of terminal selector combinations in space and time. a) Schematic of how the Wnt asymmetry pathway can be integrated with existing TFs to generate a novel regulatory state during every cell division (adapted from Bertrand 2016). The asymmetry in POP-1 and SYS-1 results in distinct transcriptional outputs in the anterior vs the posterior daughter cell. Note that this schematic is highly simplified and POP-1 in the anterior cell can also activate or repress targets (Murgan and Bertrand 2015). b) Specification of the AIY neurons illustrates a number of points described in the text. The vertical axis denotes time. Transient expression of a trigger, REF-2, is integrated with the Wnt asymmetry pathway and autoactivation of the terminal selectors TTX-3 and CEH-10 to result in specific and robust activation in the posterior cell. This distinguishes the SMDD (anterior) from the AIY (posterior) neurons. c) The autoactivation mechanism of che-1 has been proposed to be sensitive to fluctuations in the CHE-1 protein by preferential activation of its own locus (Traets et al. 2021). d) The differentiation of the left and right ASE neurons also illustrates a number of mechanisms described in the text. These 2 neurons derive from lineages that diverge at the 4-cell stage owing to the first Notch induction and represent one of the best described examples of convergence. The point where the lineages converge is marked with a dashed line. The converging branches generate 11 pairs of bilaterally symmetric neurons and 2 pairs of bilaterally symmetric glia. The early lineage asymmetry is integrated with the terminal selector CHE-1 in the form of differential chromatin states of the lsy-6 locus. This determines whether lsy-6 is expressed (ASEL) or not (ASER) and the downstream acquisition of the respective terminal gene batteries (Hobert 2014) (Fig. 7a).
Fig. 7.
Fig. 7.
Repressor-based mechanisms for neuronal diversification. a) Schematic of the double-repressor interactions that result in ASE asymmetry. The miRNA lsy-6 in ASEL represses the production of the TF COG-1. cog-1 is transcribed in both ASEs but only produces COG-1 protein in ASER where lsy-6 is absent. COG-1 acts with the corepressor Groucho/UNC-37 to repress transcription of die-1, which encodes another TF. The mutually exclusive expression of COG-1 and DIE-1 define downstream molecular asymmetries that determine the asymmetric sensory function of the 2 ASEs. b) Scheme of the repressor-based diversification of distinct motor neuron classes. All classes rely on the terminal selector UNC-3 for their differentiation, but each class expresses a distinct combination of repressors that counteract the action of UNC-3 on specific gene batteries (Kerk et al. 2017). c) The action of the terminal selector UNC-86 in the ALM and BDU sister neurons is diversified by the asymmetric expression of MEC-3 in ALM. In the absence of MEC-3, UNC-86 acts cooperatively with PAG-3 to activate BDU-specific gene expression. In ALM, MEC-3 binds UNC-86, which now activates the ALM-specific battery and is titrated away from PAG-3-dependent genes (Gordon and Hobert 2015). d) The miRNA miR-791 is specifically expressed in the BAG, AFD, and ASE neurons, where it posttranscriptionally represses 2 otherwise ubiquitously transcribed genes, cah-3 and akap-1. This repression is necessary in the BAG neurons to elicit the correct avoidance response to high CO2 levels (Drexel et al. 2016). e) Key components of the heterochronic pathway and their regulatory interactions (Ambros 2000; Ketting and Cochella 2021). Proteins are in blue; regulatory RNAs are in red and include the miRNAs lin-4 and let-7 and the lep-5 lncRNA that associates with Makorin/LEP-2 (Herrera et al. 2016; Kiontke et al. 2019). LIN-14, HBL-1, and LIN-29 are TF outputs of the pathway that are integrated with other TFs (e.g. terminal selectors) on the cis-regulatory regions of neuronal genes discussed in the text.
Fig. 8.
Fig. 8.
Environmental effects on neuron diversity. a) Different environmental triggers are integrated into gene expression changes through parallel modules acting in the neuron. b) L4 expression data of signal activated TFs and some examples of terminal selectors in sensory neurons. Signal-activated TFs, such as MEF-2, CRH-1, and DAF-16, are broadly expressed in the nervous system; however, they produce neuron class-specific responses acting together with terminal selectors that show a more restricted pattern of expression. Data source CENGEN. c) The 2 illustrated examples correspond to those described in the text. CRMs of plastic effector genes can integrate input from signal-regulated TFs as well as terminal selectors. ADL expression of srh-234 is directly regulated by the HLH-4 terminal selector but upon starvation is repressed by the MEF-2 TF. tph-1 expression in the ADF neuron is plastic to several environmental conditions, and pathogen exposure induces tph-1 expression through the activity of the LAG-1 ADF terminal selector.
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