The Evolutionarily Conserved LIM Homeodomain Protein LIM-4/LHX6 Specifies the Terminal Identity of a Cholinergic and Peptidergic C. elegans Sensory/Inter/Motor Neuron-Type

The expression of specific transcription factors determines the differentiated features of postmitotic neurons. However, the mechanism by which specific molecules determine neuronal cell fate and the extent to which the functions of transcription factors are conserved in evolution are not fully understood. In C. elegans, the cholinergic and peptidergic SMB sensory/inter/motor neurons innervate muscle quadrants in the head and control the amplitude of sinusoidal movement. Here we show that the LIM homeobox protein LIM-4 determines neuronal characteristics of the SMB neurons. In lim-4 mutant animals, expression of terminal differentiation genes, such as the cholinergic gene battery and the flp-12 neuropeptide gene, is completely abolished and thus the function of the SMB neurons is compromised. LIM-4 activity promotes SMB identity by directly regulating the expression of the SMB marker genes via a distinct cis-regulatory motif. Two human LIM-4 orthologs, LHX6 and LHX8, functionally substitute for LIM-4 in C. elegans. Furthermore, C. elegans LIM-4 or human LHX6 can induce cholinergic and peptidergic characteristics in the human neuronal cell lines. Our results indicate that the evolutionarily conserved LIM-4/LHX6 homeodomain proteins function in generation of precise neuronal subtypes.

• Publication year

  2015

• Venue

  PLoS Genetics

• Publication date

  2015-08-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pgen.1005480PMID 26305787PMCID 4549117
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• [Caenorhabditis elegans].

  2020cited by this paper
• Transcriptional coordination of synaptogenesis and neurotransmitter signaling.

  2015cited by this paper
• The LIM and POU homeobox genes ttx-3 and unc-86 act as terminal selectors in distinct cholinergic and serotonergic neuron types

  2014cited by this paper
• Maintenance of postmitotic neuronal cell identity

  2014cited by this paper
• Isl1 Directly Controls a Cholinergic Neuronal Identity in the Developing Forebrain and Spinal Cord by Forming Cell Type-Specific Complexes

  2014cited by this paper
• Upregulation of Lhx8 increase VAChT expression and ACh release in neuronal cell line SHSY5Y.

  2014cited by this paper
• Lhx6 directly regulates Arx and CXCR7 to determine cortical interneuron fate and laminar position.

  2014cited by this paper
• LIM-homeobox gene Lhx8 promote the differentiation of hippocampal newborn neurons into cholinergic neurons in vitro

  2013cited by this paper
• Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology.

  2013cited by this paper
• Modular control of glutamatergic neuronal identity in C. elegans by distinct homeodomain proteins.

  2013influential reference
• Lhx8 promote differentiation of hippocampal neural stem/progenitor cells into cholinergic neurons in vitro

  2012cited by this paper
• Transcription factor LIM homeobox 7 (Lhx7) maintains subtype identity of cholinergic interneurons in the mammalian striatum

  2012cited by this paper
• Recognition models to predict DNA-binding specificities of homeodomain proteins

  2012cited by this paper
• Regulation of terminal differentiation programs in the nervous system.

  2011cited by this paper
• Homeodomain subtypes and functional diversity.

  2011cited by this paper
• Lhx6 and Lhx8 coordinately induce neuronal expression of Shh that controls the generation of interneuron progenitors.

  2011cited by this paper
• Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene

  2011influential reference
• Early evolution of the LIM homeobox gene family

  2010cited by this paper
• The HMX/NKX homeodomain protein MLS-2 specifies the identity of the AWC sensory neuron type via regulation of the ceh-36 Otx gene in C. elegans

  2010cited by this paper
• Comparison between proliferative and neuron-like SH-SY5Y cells as an in vitro model for Parkinson disease studies.

  2010cited by this paper
• LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into cholinergic and GABAergic striatal interneurons

  2009cited by this paper
• Wnt-Ror signaling to SIA and SIB neurons directs anterior axon guidance and nerve ring placement in C. elegans

  2009influential reference
• The C. elegans Tailless/TLX transcription factor nhr-67 controls neuronal identity and left/right asymmetric fate diversification

  2009cited by this paper
• Cis‐regulatory mechanisms of gene expression in an olfactory neuron type in Caenorhabditis elegans

  2009cited by this paper
• From the Cover: Gene Networks in Development and Evolution Special Feature Sackler Colloquium: Regulatory logic of neuronal diversity: Terminal selector genes and selector motifs

  2008cited by this paper
• Identification of major classes of cholinergic neurons in the nematode Caenorhabditis elegans

  2008influential reference
• Neuropeptides.

  2008cited by this paper
• Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites.

  2008cited by this paper
• Spatial and temporal specification of neural fates by transcription factor codes

  2007cited by this paper
• The embryonic cell lineage of the nematode Halicephalobus gingivalis (Nematoda: Cephalobina: Panagrolaimoidea)

  2007cited by this paper
• A Distributed Chemosensory Circuit for Oxygen Preference in C. elegans

  2006cited by this paper
• INAUGURAL ARTICLE by a Recently Elected Academy Member:A circuit for navigation in Caenorhabditis elegans

  2005cited by this paper
• Cell-type specific regulation of serotonergic identity by the C. elegans LIM-homeodomain factor LIM-4.

  2005influential reference
• The C. elegans nuclear receptor gene fax-1 and homeobox gene unc-42 coordinate interneuron identity by regulating the expression of glutamate receptor subunits and other neuron-specific genes.

  2005cited by this paper
• The evolution of homeobox genes: Implications for the study of brain development.

  2005cited by this paper
• Genomic cis-regulatory architecture and trans-acting regulators of a single interneuron-specific gene battery in C. elegans.

  2004cited by this paper
• Feeding status and serotonin rapidly and reversibly modulate a Caenorhabditis elegans chemosensory circuit.

  2004cited by this paper
• The LIM homeobox gene, L3/Lhx8, is necessary for proper development of basal forebrain cholinergic neurons

  2004cited by this paper
• Expression and regulation of an FMRFamide‐related neuropeptide gene family in Caenorhabditis elegans

  2004cited by this paper
• The LIM-homeobox gene Lhx8 is required for the development of many cholinergic neurons in the mouse forebrain

  2003cited by this paper
• Otx/otd homeobox genes specify distinct sensory neuron identities in C. elegans.

  2003cited by this paper
• Caenorhabditis elegans cog-1 locus encodes GTX/Nkx6.1 homeodomain proteins and regulates multiple aspects of reproductive system development.

  2002cited by this paper
• The Caenorhabditis elegans odr-2 gene encodes a novel Ly-6-related protein required for olfaction.

  2001cited by this paper
• The lin-11 LIM homeobox gene specifies olfactory and chemosensory neuron fates in C. elegans.

  2001cited by this paper
• A regulatory cascade of three homeobox genes, ceh-10, ttx-3 and ceh-23, controls cell fate specification of a defined interneuron class in C. elegans.

  2001influential reference
• Identification and characterization of the high-affinity choline transporter

  2000cited by this paper
• The homeodomain protein CePHOX2/CEH-17 controls antero-posterior axonal growth in C. elegans.

  2000influential reference
• Olfaction and odor discrimination are mediated by the C. elegans guanylyl cyclase ODR-1.

  2000cited by this paper
• Functions of LIM-homeobox genes.

  2000cited by this paper
• Alternative olfactory neuron fates are specified by the LIM homeobox gene lim-4.

  1999influential reference
• Redistribution of F-actin and large dense-cored vesicles in the human neuroblastoma SH-SY5Y in response to secretagogues and protein kinase Calpha activation.

  1999cited by this paper
• Muscle and nerve-specific regulation of a novel NK-2 class homeodomain factor in Caenorhabditis elegans.

  1998influential reference
• OSM-9, A Novel Protein with Structural Similarity to Channels, Is Required for Olfaction, Mechanosensation, and Olfactory Adaptation inCaenorhabditis elegans

  1997cited by this paper
• LIM domain proteins.

  1995cited by this paper
• The Caenorhabditis elegans unc-17 gene: a putative vesicular acetylcholine transporter.

  1993cited by this paper
• Chemosensory neurons with overlapping functions direct chemotaxis to multiple chemicals in C. elegans.

  1991cited by this paper
• A modular set of lacZ fusion vectors for studying gene expression in Caenorhabditis elegans.

  1990cited by this paper
• [Genetics of Caenorhabditis elegans].

  1989cited by this paper
• The structure of the nervous system of the nematode Caenorhabditis elegans.

  1986influential reference
• Polyploid tissues in the nematode Caenorhabditis elegans.

  1985influential reference
• The embryonic cell lineage of the nematode Caenorhabditis elegans.

  1983cited by this paper
• Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones.

  1978cited by this paper
• The genetics of Caenorhabditis elegans.

  1974cited by this paper

• PIEZO acts in an intestinal valve to regulate swallowing in C. elegans

  2024cites this paper
• A FMRFamide-like neuropeptide FLP-12 signaling regulates head locomotive behaviors in Caenorhabditis elegans

  2024cites this paper
• Neural Sequences Underlying Directed Turning in C. elegans

  2024cites this paper
• Neuronal sensorimotor integration guiding salt concentration navigation in Caenorhabditis elegans

  2024cites this paper
• Dauer quiescence as well as continuity of the life cycle after dauer-exit in Caenorhabditis elegans are dependent on the endoribonuclease activity of XRN-2

  2022cites this paper
• The CCAAT-box transcription factor, NF-Y complex, mediates the specification of the IL1 neurons in C. elegans

  2022cites this paper
• The transcriptional corepressor CTBP-1 acts with the SOX family transcription factor EGL-13 to maintain AIA interneuron cell identity in Caenorhabditis elegans

  2022cites this paper
• The Prop1-like homeobox gene unc-42 specifies the identity of synaptically connected neurons

  2021cites this paper
• In silico analysis of the transcriptional regulatory logic of neuronal identity specification throughout the C. elegans nervous system

  2021cites this paper
• The transcriptional corepressor CTBP-1 acts with the SOX family transcription factor EGL-13 to maintain AIA interneuron cell identity in C. elegans

  2021cites this paper
• Transcription Factors That Control Behavior—Lessons From C. elegans

  2021cites this paper
• LDB1 and the SWI/SNF complex participate in both transcriptional activation and repression by Caenorhabditis elegans BLIMP1/PRDM1.

  2020cites this paper
• Circuit transcription factors in Caenorhabditis elegans

  2020cites this paper
• Genome-wide RNAi screen for regulators of UPRmt in Caenorhabditis elegans mutants with defects in mitochondrial fusion

  2020cites this paper
• Neuronal identity control by terminal selectors in worms, flies, and chordates.

  2019cites this paper
• Isolation and partial characterization of three members of the GGR-1 family in the parasitic nematode Haemonchus contortus

  2019cites this paper
• Neuropeptides encoded by nlp-49 modulate locomotion, arousal and egg-laying behaviours in Caenorhabditis elegans via the receptor SEB-3

  2018cites this paper
• A sensory-motor neuron type mediates proprioceptive coordination of steering in C. elegans via two TRPC channels

  2018cites this paper
• LHX6, An Independent Prognostic Factor, Inhibits Lung Adenocarcinoma Progression through Transcriptional Silencing of β-catenin

  2017cites this paper
• Early Pheromone Experience Modifies a Synaptic Activity to Influence Adult Pheromone Responses of C. elegans.

  2017cites this paper
• A map of terminal regulators of neuronal identity in Caenorhabditis elegans

  2016cites this paper
• A cellular and regulatory map of the cholinergic nervous system of C. elegans

  2015cites this paper