The Groucho-like transcription factor UNC-37 functions with the neural specificity gene unc-4 to govern motor neuron identity in C. elegans

Development ◽  
1997 ◽  
Vol 124 (9) ◽  
pp. 1699-1709 ◽  
Author(s):  
A. Pflugrad ◽  
J.Y. Meir ◽  
T.M. Barnes ◽  
D.M. Miller
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Target Genes ◽  
Protein Domain ◽  
Homeodomain Protein ◽  
Missense Mutations ◽  
C Elegans ◽  
Expression Of Genes ◽  
Wd Repeat ◽  
Normal Input

Groucho and Tup1 are members of a conserved family of WD repeat proteins that interact with specific transcription factors to repress target genes. Here we show that mutations in WD domains of the Groucho-like protein, UNC-37, affect a motor neuron trait that also depends on UNC-4, a homeodomain protein that controls neuronal specificity in Caenorhabditis elegans. In unc-4 mutants, VA motor neurons assume the pattern of synaptic input normally reserved for their lineal sister cells, the VB motor neurons; the loss of normal input to the VAs produces a distinctive backward movement defect. Substitution of a conserved residue (H to Y) in the fifth WD repeat in unc-37(e262) phenocopies the Unc-4 movement defect. Conversely, an amino acid change (E to K) in the sixth WD repeat of UNC-37 is a strong suppressor of unc-37(e262) and of specific unc-4 missense mutations. We have previously shown that UNC-4 expression in the VA motor neurons specifies the wild-type pattern of presynaptic input. Here we demonstrate that UNC-37 is also expressed in the VAs and that unc-37 activity in these neurons is sufficient to restore normal movement to unc-37(e262) animals. We propose that UNC-37 and UNC-4 function together to prevent expression of genes that define the VB pattern of synaptic inputs and thereby generate connections specific to the VA motor neurons. In addition, we show that the WD repeat domains of UNC-37 and of the human homolog, TLE1, are functionally interchangeable in VA motor neurons which suggests that this highly conserved protein domain may also specify motor neuron identity and synaptic choice in more complex nervous systems.

C. elegans unc-4 gene encodes a homeodomain protein that determines the pattern of synaptic input to specific motor neurons

Nature ◽  
1992 ◽  
Vol 355 (6363) ◽  
pp. 841-845 ◽  
Author(s):  
David M. Miller ◽  
Michael M. Shen ◽  
Caroline E. Shamu ◽  
Thomas R. Bürglin ◽  
Gary Ruvkun ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Synaptic Input ◽  
Homeodomain Protein ◽  
C Elegans

The control of rostrocaudal pattern in the developing spinal cord: specification of motor neuron subtype identity is initiated by signals from paraxial mesoderm

Development ◽  
1998 ◽  
Vol 125 (6) ◽  
pp. 969-982 ◽  
Author(s):  
M. Ensini ◽  
T.N. Tsuchida ◽  
H.G. Belting ◽  
T.M. Jessell
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neural Tube ◽  
Motor Behavior ◽  
Neural Tube Closure ◽  
Paraxial Mesoderm ◽  
Homeodomain Protein ◽  
Mesodermal Cell ◽  
Developing Spinal Cord

The generation of distinct classes of motor neurons is an early step in the control of vertebrate motor behavior. To study the interactions that control the generation of motor neuron subclasses in the developing avian spinal cord we performed in vivo grafting studies in which either the neural tube or flanking mesoderm were displaced between thoracic and brachial levels. The positional identity of neural tube cells and motor neuron subtype identity was assessed by Hox and LIM homeodomain protein expression. Our results show that the rostrocaudal identity of neural cells is plastic at the time of neural tube closure and is sensitive to positionally restricted signals from the paraxial mesoderm. Such paraxial mesodermal signals appear to control the rostrocaudal identity of neural tube cells and the columnar subtype identity of motor neurons. These results suggest that the generation of motor neuron subtypes in the developing spinal cord involves the integration of distinct rostrocaudal and dorsoventral patterning signals that derive, respectively, from paraxial and axial mesodermal cell groups.

The C. elegans NeuroD homolog cnd-1 functions in multiple aspects of motor neuron fate specification

Development ◽  
2000 ◽  
Vol 127 (19) ◽  
pp. 4239-4252 ◽  
Author(s):  
S. Hallam ◽  
E. Singer ◽  
D. Waring ◽  
Y. Jin
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Expression Patterns ◽  
Loss Of Function ◽  
Variable Expression ◽  
C Elegans ◽  
Helix Loop Helix ◽  
Ventral Cord ◽  
Bhlh Proteins ◽  
Neuronal Type

The basic helix-loop-helix transcription factor NeuroD (Neurod1) has been implicated in neuronal fate determination, differentiation and survival. Here we report the expression and functional analysis of cnd-1, a C. elegans NeuroD homolog. cnd-1 expression was first detected in neuroblasts of the AB lineage in 14 cell embryos and maintained in many neuronal descendants of the AB lineage during embryogenesis, diminishing in most terminally differentiated neurons prior to hatching. Specifically, cnd-1 reporter genes were expressed in the precursors of the embryonic ventral cord motor neurons and their progeny. A loss-of-function mutant, cnd-1(ju29), exhibited multiple defects in the ventral cord motor neurons. First, the number of motor neurons was reduced, possibly caused by the premature withdrawal of the precursors from mitotic cycles. Second, the strict correlation between the fate of a motor neuron with respect to its lineage and position in the ventral cord was disrupted, as manifested by the variable expression pattern of motor neuron fate specific markers. Third, motor neurons also exhibited defects in terminal differentiation characteristics including axonal morphology and synaptic connectivity. Finally, the expression patterns of three neuronal type-specific transcription factors, unc-3, unc-4 and unc-30, were altered. Our data suggest that cnd-1 may specify the identity of ventral cord motor neurons both by maintaining the mitotic competence of their precursors and by modulating the expression of neuronal type-specific determination factors. cnd-1 appears to have combined the functions of several vertebrate neurogenic bHLH proteins and may represent an ancestral form of this protein family.

scholarly journals A Comprehensive Profile of ChIP-Seq-Based Olig2 Target Genes in Motor Neuron Progenitor Cells Suggests the Possible Involvement of Olig2 in the Pathogenesis of Amyotrophic Lateral Sclerosis

2015 ◽  
Vol 7 ◽  
pp. JCNSD.S23210 ◽  
Author(s):  
Jun-Ichi Satoh ◽  
Naohiro Asahina ◽  
Shouta Kitano ◽  
Yoshihiro Kino
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Progenitor Cells ◽  
Motor Neurons ◽  
Target Genes ◽  
Molecular Networks ◽  
Bhlh Transcription Factor ◽  
Wide Range ◽  
Lateral Sclerosis

Background Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease that primarily affects motor neurons in the cerebral cortex and the spinal cord. Recent evidence indicates that dysfunction of oligodendrocytes is implicated in the pathogenesis of ALS. The basic helix–loop–helix (bHLH) transcription factor Olig2 plays a pivotal role in the development of both motor neurons and oligodendrocytes in the progenitor of motor neuron (pMN) domain of the spinal cord, supporting evidence for the shared motor neuron/oligodendrocyte lineage. However, a comprehensive profile of Olig2 target genes in pMNs and oligodendrocyte progenitor cells (OPCs) with relevance to the pathogenesis of ALS remains to be characterized. Methods By analyzing the ChIP-Seq datasets numbered SRP007566 and SRP015333 with the Strand NGS program, we identified genome-wide Olig2 target genes in pMNs and OPCs, followed by molecular network analysis using three distinct bioinformatics tools. Results We identified 5966 Olig2 target genes in pMNs, including Nkx2.2, Pax6, Irx3, Ngn2, Zep2 (Cip1), Trp3, Mnx1 (Hb9), and Cdkn1a, and 1553 genes in OPCs. The genes closely related to the keyword “alternative splicing” were enriched in the set of 740 targets overlapping between pMNs and OPCs. Furthermore, approximately one-third of downregulated genes in purified motor neurons of presymptomatic mutant SOD1 transgenic mice and in lumbar spinal cord tissues of ALS patients corresponded to Olig2 target genes in pMNs. Molecular networks of Olig2 target genes indicate that Olig2 regulates a wide range of genes essential for diverse neuronal and glial functions. Conclusions These observations lead to a hypothesis that aberrant regulation of Olig2 function, by affecting biology of both motor neurons and oligodendrocytes, might be involved in the pathogenesis of ALS.

scholarly journals Computing temporal sequences associated with dynamic patterns on the C. elegans connectome

2020 ◽  
Author(s):  
Vivek Kurien George ◽  
Francesca Puppo ◽  
Gabriel A. Silva
Keyword(s):  
Motor Neuron ◽  
Signaling Pathways ◽  
Motor Neurons ◽  
Structural Connectivity ◽  
Global Dynamics ◽  
C Elegans ◽  
Embedded Network ◽  
Chemosensory Neuron ◽  
Temporal Sequences ◽  
Contralateral Motor

AbstractUnderstanding how the structural connectivity of a network constrains the dynamics it is able to support is a very active and open area of research. We simulated the plausible dynamics resulting from the known C. elegans connectome using a recent model and theoretical analysis that computes the dynamics of neurobiological networks by focusing on how local interactions among connected neurons give rise to the global dynamics in an emergent way, independent of the biophysical or molecular details of the cells themselves. We studied the dynamics which resulted from stimulating a chemosensory neuron (ASEL) in a known feeding circuit, both in isolation and embedded in the full connectome. We show that contralateral motor neuron activations in ventral (VB) and dorsal (DB) classes of motor neurons emerged from the simulations, which are qualitatively similar to rhythmic motor neuron firing pattern associated with locomotion of the worm. One interpretation of these results is that there is an inherent - and we propose - purposeful structural wiring to the C. elegans connectome that has evolved to serve specific behavioral functions. To study network signaling pathways responsible for the dynamics we developed an analytic framework that constructs Temporal Sequences (TSeq), time-ordered walks of signals on graphs. We found that only 5% of TSeq are preserved between the isolated feeding network relative to its embedded counterpart. The remaining 95% of signaling pathways computed in the isolated network are not present in the embedded network. This suggests a cautionary note for computational studies of isolated neurobiological circuits and networks.

scholarly journals Establishment and maintenance of motor neuron identity via temporal modularity in terminal selector function

2020 ◽  
Author(s):  
Yinan Li ◽  
Anthony Osuma ◽  
Edgar Correa ◽  
Munachiso A. Okebalama ◽  
Pauline Dao ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Genome Engineering ◽  
Life Stages ◽  
C Elegans ◽  
Neuronal Identity ◽  
Protein Classes ◽  
Selector Function

ABSTRACTTerminal selectors are transcription factors (TFs) that establish during development and maintain throughout life post-mitotic neuronal identity. We previously showed that UNC-3/Ebf, the terminal selector of C. elegans cholinergic motor neurons (MNs), acts indirectly to prevent alternative neuronal identities (Feng et al., 2020). Here, we globally identify the direct targets of UNC-3. Unexpectedly, we find that the suite of UNC-3 targets in MNs is modified across different life stages, revealing “temporal modularity” in terminal selector function. In all larval and adult stages examined, UNC-3 is required for continuous expression of various protein classes (e.g., receptors, transporters) critical for MN function. However, only in late larvae and adults, UNC-3 is required to maintain expression of MN-specific TFs. Minimal disruption of UNC-3’s temporal modularity via genome engineering affects locomotion. Another C. elegans terminal selector (UNC-30/Pitx) also exhibits temporal modularity, supporting the potential generality of this mechanism for the control of neuronal identity.

scholarly journals Integrins Have Cell-Type-Specific Roles in the Development of Motor Neuron Connectivity

2019 ◽  
Vol 7 (3) ◽  
pp. 17 ◽  
Author(s):  
Devyn Oliver ◽  
Emily Norman ◽  
Heather Bates ◽  
Rachel Avard ◽  
Monika Rettler ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Adhesion ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuron Development ◽  
Wild Type ◽  
Cell Type ◽  
C Elegans ◽  
Cell Type Specific ◽  
Two Phases

Formation of the nervous system requires a complex series of events including proper extension and guidance of neuronal axons and dendrites. Here we investigate the requirement for integrins, a class of transmembrane cell adhesion receptors, in regulating these processes across classes of C. elegans motor neurons. We show α integrin/ina-1 is expressed by both GABAergic and cholinergic motor neurons. Despite this, our analysis of hypomorphic ina-1(gm144) mutants indicates preferential involvement of α integrin/ina-1 in GABAergic commissural development, without obvious involvement in cholinergic commissural development. The defects in GABAergic commissures of ina-1(gm144) mutants included both premature termination and guidance errors and were reversed by expression of wild type ina-1 under control of the native ina-1 promoter. Our results also show that α integrin/ina-1 is important for proper outgrowth and guidance of commissures from both embryonic and post-embryonic born GABAergic motor neurons, indicating an ongoing requirement for integrin through two phases of GABAergic neuron development. Our findings provide insights into neuron-specific roles for integrin that would not be predicted based solely upon expression analysis.

Control of hindbrain motor neuron differentiation by the homeobox gene Phox2b

Development ◽  
2000 ◽  
Vol 127 (7) ◽  
pp. 1349-1358 ◽  
Author(s):  
A. Pattyn ◽  
M. Hirsch ◽  
C. Goridis ◽  
J.F. Brunet
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Early Stage ◽  
Control Point ◽  
Homeobox Gene ◽  
Homeodomain Protein ◽  
Loss Of Function ◽  
Dorsoventral Patterning ◽  
Cns Neurons ◽  
Mantle Layer

Motor neurons are a widely studied model of vertebrate neurogenesis. They can be subdivided in somatic, branchial and visceral motor neurons. Recent studies on the dorsoventral patterning of the rhombencephalon have implicated the homeobox genes Pax6 and Nkx2.2 in the early divergence of the transcriptional programme of hindbrain somatic and visceral motor neuronal differentiation. We provide genetic evidence that the paired-like homeodomain protein Phox2b is required for the formation of all branchial and visceral, but not somatic, motor neurons in the hindbrain. In mice lacking Phox2b, both the generic and subtype-specific programs of motoneuronal differentiation are disrupted at an early stage. Most motor neuron precursors die inside the neuroepithelium while those that emigrate to the mantle layer fail to switch on early postmitotic markers and to downregulate neuroepithelial markers. Thus, the loss of function of Phox2b in hindbrain motor neurons exemplifies a novel control point in the generation of CNS neurons.

scholarly journals Establishment and maintenance of motor neuron identity via temporal modularity in terminal selector function

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yinan Li ◽  
Anthony Osuma ◽  
Edgar Correa ◽  
Munachiso A Okebalama ◽  
Pauline Dao ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Genome Engineering ◽  
Life Stages ◽  
C Elegans ◽  
Neuronal Identity ◽  
Protein Classes ◽  
Selector Function

Terminal selectors are transcription factors (TFs) that establish during development and maintain throughout life post-mitotic neuronal identity. We previously showed that UNC-3/Ebf, the terminal selector of C. elegans cholinergic motor neurons (MNs), acts indirectly to prevent alternative neuronal identities (Feng et al., 2020). Here, we globally identify the direct targets of UNC-3. Unexpectedly, we find that the suite of UNC-3 targets in MNs is modified across different life stages, revealing ‘temporal modularity’ in terminal selector function. In all larval and adult stages examined, UNC-3 is required for continuous expression of various protein classes (e.g. receptors, transporters) critical for MN function. However, only in late larvae and adults, UNC-3 is required to maintain expression of MN-specific TFs. Minimal disruption of UNC-3’s temporal modularity via genome engineering affects locomotion. Another C. elegans terminal selector (UNC-30/Pitx) also exhibits temporal modularity, supporting the potential generality of this mechanism for the control of neuronal identity.

scholarly journals A descending pathway facilitates undulatory wave propagation in Caenorhabditis elegans through gap junctions

2017 ◽  
Author(s):  
Tianqi Xu ◽  
Jing Huo ◽  
Shuai Shao ◽  
Michelle Po ◽  
Taizo Kawano ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Gap Junctions ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Central Pattern Generators ◽  
The Body ◽  
C Elegans ◽  
Bending Waves ◽  
Forward Locomotion ◽  
Type Motor

Descending signals from the brain play critical roles in controlling and modulating locomotion kinematics. In the Caenorhabditis elegans nervous system, descending AVB premotor interneurons exclusively form gap junctions with B-type motor neurons that drive forward locomotion. We combined genetic analysis, optogenetic manipulation, and computational modeling to elucidate the function of AVB-B gap junctions during forward locomotion. First, we found that some B-type motor neurons generated intrinsic rhythmic activity, constituting distributed central pattern generators. Second, AVB premotor interneurons drove bifurcation of B-type motor neuron dynamics, triggering their transition from stationary to oscillatory activity. Third, proprioceptive couplings between neighboring B-type motor neurons entrained the frequency of body oscillators, forcing coherent propagation of bending waves. Despite substantial anatomical differences between the worm motor circuit and those in higher model organisms, we uncovered converging principles that govern coordinated locomotion.Significance StatementA deep understanding of the neural basis of motor behavior must integrate neuromuscular dynamics, mechanosensory feedback, as well as global command signals, to predict behavioral dynamics. Here, we report on an integrative approach to defining the circuit logic underlying coordinated locomotion in C. elegans. Our combined experimental and computational analysis revealed that (1) motor neurons in C. elegans could function as intrinsic oscillators; (2) Descending inputs and proprioceptive couplings work synergistically to facilitate the sequential activation of motor neuron activities, allowing bending waves to propagate efficiently along the body. Our work thus represents a key step towards an integrative view of animal locomotion.

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