scholarly journals An ancient role for Collier/Olf/Ebf (COE)-type transcription factors in axial motor neuron development

2018 ◽  
Author(s):  
Catarina Catela ◽  
Edgar Correa ◽  
Jihad Aburas ◽  
Laura Croci ◽  
G. Giacomo Consalez ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Motor Neuron ◽  
Molecular Mechanisms ◽  
Neuron Development ◽  
Spinal Alignment ◽  
Knock Out ◽  
Transgenic Expression ◽  
C Elegans ◽  
Functional Conservation ◽  
Motor Circuits

ABSTRACTBackgroundMammalian motor circuits display remarkable cellular diversity with hundreds of motor neuron (MN) subtypes innervating hundreds of different muscles. Extensive research on limb muscle-innervating MNs has begun to elucidate the genetic programs that control animal locomotion. In striking contrast, the molecular mechanisms underlying the development of axial muscle-innervating MNs, which control breathing and spinal alignment, are poorly studied.MethodsOur previous studies indicated that the function of the Collier/Olf/Ebf (COE) family of transcription factors (TFs) in axial MN development may be conserved from nematodes to simple chordates. Here, we examine the expression pattern of all four mouse COE family members (mEbf1-mEbf4) in spinal MNs and employ genetic approaches in both nematodes and mice to investigate their function in axial MN development.ResultsWe report that mEbf1 and mEbf2 are expressed in distinct MN clusters (termed “columns”) that innervate different axial muscles. Mouse Ebf1 is expressed in MNs of the hypaxial motor column (HMC), which is necessary for breathing, while mEbf2 is expressed in MNs of the medial motor column (MMC) that control spinal alignment. Our characterization of Ebf2 knock-out mice revealed a requirement for Ebf2 in the differentiation of a subset of MMC MNs, indicating molecular diversity within MMC neurons. Intriguingly, transgenic expression of mEbf1 or mEbf2 can rescue axial MN differentiation and locomotory defects in nematodes (Caenorhabditis elegans) lacking unc-3, the sole C. elegans ortholog of the COE family, suggesting functional conservation among mEbf1, mEbf2 and nematode UNC-3.ConclusionsThese findings support the hypothesis that the genetic programs controlling axial MN development are deeply conserved across species, and further advance our understanding of such programs by revealing an essential role for Ebf2 in mouse axial MNs. Because human mutations in COE ortholgs lead to neurodevelopmental disorders characterized by motor developmental delay, our findings may advance our understanding of these human conditions.

scholarly journals Groucho/TLE opposes axial to hypaxial motor neuron development

2020 ◽  
Author(s):  
Adèle Salin-Cantegrel ◽  
Rola Dali ◽  
Jae Woong Wang ◽  
Marielle Beaulieu ◽  
Mira Deshmukh ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
List Type ◽  
Neuron Development ◽  
In Ovo ◽  
Motor Circuits ◽  
Axial Muscles ◽  
Muscle Innervation

ABSTRACTSpinal cord motor neuron diversity and the ensuing variety of motor circuits allow for the processing of elaborate muscular behaviours such as body posture and breathing. Little is known, however, about the molecular mechanisms behind the specification of axial and hypaxial motor neurons controlling postural and respiratory functions respectively. Here we show that the Groucho/TLE (TLE) transcriptional corepressor is a multi-step regulator of axial and hypaxial motor neuron diversification in the developing spinal cord. TLE first promotes axial motor neuron specification at the expense of hypaxial identity by cooperating with non-canonical WNT5A signalling within the motor neuron progenitor domain. TLE further acts during post-mitotic motor neuron diversification to promote axial motor neuron topology and axonal connectivity whilst suppressing hypaxial traits. These findings provide evidence for essential and sequential roles of TLE in the spatial and temporal coordination of events regulating the development of motor neurons influencing posture and controlling respiration.HIGHLIGHTSGroucho/TLE mediates non-canonical WNT signalling in developing motor neuronsNon canonical WNT:TLE pathway regulates thoracic motor neuron diversificationTLE promotes axial while inhibiting hypaxial motor neuron developmentTLE influences developing motor neuron topology and muscle innervationIN BRIEFSalin-Cantegrel et al use in ovo engineered approaches to show that a non-canonical WNT:TLE pathway coordinates temporally and spatially separated elements of motor neuron diversification, repressing hypaxial motor neuron development to promote the axial fate.GRAPHICAL ABSTRACTTLE contribution to the development of thoracic somatic motor columnsProgenitor cells in the ventral pMN domain are exposed to higher concentrations of non-canonical WNTs and express more TLE. Cooperation of non-canonical WNTs and TLE renders ventral pMN progenitors refractory to a respiratory MN fate, thereby contributing to the separation of MMC and RMC MN lineages. Differentiating MNs that maintain high TLE expression also maintain LHX3 expression, adopt axial motor neuron topology and connect to axial muscles. TLE activity in differentiating MMC MNs prevents the acquisition of respiratory MN topology and innervation traits.

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.

scholarly journals Transcriptome analysis reveals rice MADS13 as an important repressor of the carpel development pathway in ovules

2020 ◽  
Author(s):  
Michela Osnato ◽  
Elia Lacchini ◽  
Alessandro Pilatone ◽  
Ludovico Dreni ◽  
Andrea Grioni ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Protein Complexes ◽  
Female Sterility ◽  
Homeotic Genes ◽  
Ovule Development ◽  
Knock Out ◽  
Regulatory Pathways ◽  
Genes Encoding

Abstract In angiosperms, floral homeotic genes encoding MADS-domain transcription factors regulate the development of floral organs. Specifically, members of the SEPALLATA (SEP) and AGAMOUS (AG) subfamilies form higher-order protein complexes to control floral meristem determinacy and to specify the identity of female reproductive organs. In rice, the AG subfamily gene OsMADS13 is intimately involved in the determination of ovule identity, since knock-out mutant plants develop carpel-like structures in place of ovules, resulting in female sterility. Little is known about the regulatory pathways at the base of rice gynoecium development. To investigate molecular mechanisms acting downstream of OsMADS13, we obtained transcriptomes of immature inflorescences from wild-type and Osmads13 mutant plants. Among a total of 476 differentially expressed genes (DEGs), a substantial overlap with DEGs from the SEP-family Osmads1 mutant was found, suggesting that OsMADS1 and OsMADS13 may act on a common set of target genes. Expression studies and preliminary analyses of two up-regulated genes encoding Zinc-finger transcription factors indicated that our dataset represents a valuable resource for the identification of both OsMADS13 target genes and novel players in rice ovule development. Taken together, our study suggests that OsMADS13 is an important repressor of the carpel pathway during ovule development.

Molecular mechanisms regulating motor neuron development and degeneration

1999 ◽  
Vol 19 (3) ◽  
pp. 205-228 ◽  
Author(s):  
Trevor J. Kilpatrick ◽  
Merja Soilu-Hänninen
Keyword(s):  
Motor Neuron ◽  
Molecular Mechanisms ◽  
Neuron Development

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 SPOP and CUL3 Modulate the Sonic Hedgehog Signal Response Through Controlled Degradation of GLI Family Transcription Factors

2021 ◽  
Vol 9 ◽  
Author(s):  
Patricia A. Umberger ◽  
Stacey K. Ogden
Keyword(s):  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Evolutionary Divergence ◽  
Transcriptional Responses ◽  
Cubitus Interruptus ◽  
Functional Conservation ◽  
Gli Transcription Factors ◽  
Health And Disease ◽  
Key Driver ◽  
Broad Complex

The speckle-type POZ protein (SPOP) functions as a guardian of genome integrity and controls transcriptional regulation by functioning as a substrate adaptor for CUL3/RING-type E3 ubiquitin ligase complexes. SPOP-containing CUL3 complexes target a myriad of DNA-binding proteins involved in DNA repair and gene expression, and as such, are essential modulators of cellular homeostasis. GLI transcription factors are effectors of the Hedgehog (HH) pathway, a key driver of tissue morphogenesis and post-developmental homeostasis that is commonly corrupted in cancer. CUL3-SPOP activity regulates amplitude and duration of HH transcriptional responses by controlling stability of GLI family members. SPOP and GLI co-enrich in phase separated nuclear droplets that are thought to serve as hot spots for CUL3-mediated GLI ubiquitination and degradation. A similar framework exists in Drosophila, in which the Hedgehog-induced MATH (meprin and traf homology) and BTB (bric à brac, tramtrack, broad complex) domain containing protein (HIB) targets the GLI ortholog Cubitus interruptus (Ci) for Cul3-directed proteolysis. Despite this functional conservation, the molecular mechanisms by which HIB and SPOP contribute to Drosophila and vertebrate HH signaling differ. In this mini-review we highlight similarities between the two systems and discuss evolutionary divergence in GLI/Ci targeting that informs our understanding of how the GLI transcriptional code is controlled by SPOP and CUL3 in health and disease.

scholarly journals An ancient role for collier/Olf/Ebf (COE)-type transcription factors in axial motor neuron development

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Catarina Catela ◽  
Edgar Correa ◽  
Kailong Wen ◽  
Jihad Aburas ◽  
Laura Croci ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Motor Neuron ◽  
Neuron Development

scholarly journals Phrenic-specific transcriptional programs shape respiratory motor output

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Alicia N Vagnozzi ◽  
Kiran Garg ◽  
Carola Dewitz ◽  
Matthew T Moore ◽  
Jared M Cregg ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Adhesion ◽  
Motor Neuron ◽  
Molecular Mechanisms ◽  
Motor Output ◽  
Specific Cell ◽  
Premotor Neurons ◽  
Respiratory Behavior ◽  
Inspiratory Activity ◽  
Motor Actions

The precise pattern of motor neuron (MN) activation is essential for the execution of motor actions; however, the molecular mechanisms that give rise to specific patterns of MN activity are largely unknown. Phrenic MNs integrate multiple inputs to mediate inspiratory activity during breathing and are constrained to fire in a pattern that drives efficient diaphragm contraction. We show that Hox5 transcription factors shape phrenic MN output by connecting phrenic MNs to inhibitory premotor neurons. Hox5 genes establish phrenic MN organization and dendritic topography through the regulation of phrenic-specific cell adhesion programs. In the absence of Hox5 genes, phrenic MN firing becomes asynchronous and erratic due to loss of phrenic MN inhibition. Strikingly, mice lacking Hox5 genes in MNs exhibit abnormal respiratory behavior throughout their lifetime. Our findings support a model where MN-intrinsic transcriptional programs shape the pattern of motor output by orchestrating distinct aspects of MN connectivity.

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