RESUMO
Walking is the predominant locomotor behavior expressed by land-dwelling vertebrates, but it is unknown when the neural circuits that are essential for limb control first appeared. Certain fish species display walking-like behaviors, raising the possibility that the underlying circuitry originated in primitive marine vertebrates. We show that the neural substrates of bipedalism are present in the little skate Leucoraja erinacea, whose common ancestor with tetrapods existed â¼420 million years ago. Leucoraja exhibits core features of tetrapod locomotor gaits, including left-right alternation and reciprocal extension-flexion of the pelvic fins. Leucoraja also deploys a remarkably conserved Hox transcription factor-dependent program that is essential for selective innervation of fin/limb muscle. This network encodes peripheral connectivity modules that are distinct from those used in axial muscle-based swimming and has apparently been diminished in most modern fish. These findings indicate that the circuits that are essential for walking evolved through adaptation of a genetic regulatory network shared by all vertebrates with paired appendages. VIDEO ABSTRACT.
Assuntos
Proteínas Aviárias , Galinhas/fisiologia , Evolução Molecular , Proteínas de Peixes , Proteínas de Homeodomínio , Rede Nervosa/fisiologia , Rajidae/fisiologia , Fatores de Transcrição , Caminhada/fisiologia , Peixe-Zebra/fisiologia , Nadadeiras de Animais/fisiologia , Animais , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Embrião de Galinha , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Músculo Esquelético/fisiologia , Natação/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes'1-3, with a proposed role in contributing to human bipedalism4-6. Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element-inserted into an intron of the TBXT gene7-9-pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans10. Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today.
Assuntos
Processamento Alternativo , Evolução Molecular , Hominidae , Proteínas com Domínio T , Cauda , Animais , Humanos , Camundongos , Processamento Alternativo/genética , Elementos Alu/genética , Modelos Animais de Doenças , Genoma/genética , Hominidae/anatomia & histologia , Hominidae/genética , Íntrons/genética , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Fenótipo , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Cauda/anatomia & histologia , Cauda/embriologia , Éxons/genéticaRESUMO
Control of movement is a fundamental and complex task of the vertebrate nervous system, which relies on communication between circuits distributed throughout the brain and spinal cord. Many of the networks essential for the execution of basic locomotor behaviors are composed of discrete neuronal populations residing within the spinal cord. The organization and connectivity of these circuits is established through programs that generate functionally diverse neuronal subtypes, each contributing to a specific facet of motor output. Significant progress has been made in deciphering how neuronal subtypes are specified and in delineating the guidance and synaptic specificity determinants at the core of motor circuit assembly. Recent studies have shed light on the basic principles linking locomotor circuit connectivity with function, and they are beginning to reveal how more sophisticated motor behaviors are encoded. In this review, we discuss the impact of developmental programs in specifying motor behaviors governed by spinal circuits.
Assuntos
Atividade Motora/fisiologia , Rede Nervosa/fisiologia , Medula Espinal/fisiologia , AnimaisRESUMO
The chromosomally-arrayed Hox gene family plays central roles in embryonic patterning and the specification of cell identities throughout the animal kingdom. In vertebrates, the relatively large number of Hox genes and pervasive expression throughout the body has hindered understanding of their biological roles during differentiation. Studies on the subtype diversification of spinal motor neurons (MNs) have provided a tractable system to explore the function of Hox genes during differentiation, and have provided an entry point to explore how neuronal fate determinants contribute to motor circuit assembly. Recent work, using both in vitro and in vivo models of MN subtype differentiation, have revealed how patterning morphogens and regulation of chromatin structure determine cell-type specific programs of gene expression. These studies have not only shed light on basic mechanisms of rostrocaudal patterning in vertebrates, but also have illuminated mechanistic principles of gene regulation that likely operate in the development and maintenance of terminal fates in other systems.
Assuntos
Proteínas de Homeodomínio , Medula Espinal , Animais , Proteínas de Homeodomínio/metabolismo , Medula Espinal/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Diferenciação Celular/genética , Neurônios Motores/metabolismo , VertebradosRESUMO
Although Hox genes encode for conserved transcription factors (TFs), they are further divided into anterior, central and posterior groups based on their DNA-binding domain similarity. The posterior Hox group expanded in the deuterostome clade and patterns caudal and distal structures. We aimed to address how similar Hox TFs diverge to induce different positional identities. We studied Hox TF DNA-binding and regulatory activity during an in vitro motor neuron differentiation system that recapitulates embryonic development. We found diversity in the genomic binding profiles of different Hox TFs, even among the posterior group paralogs that share similar DNA-binding domains. These differences in genomic binding were explained by differing abilities to bind to previously inaccessible sites. For example, the posterior group HOXC9 had a greater ability to bind occluded sites than the posterior HOXC10, producing different binding patterns and driving differential gene expression programs. From these results, we propose that the differential abilities of posterior Hox TFs to bind to previously inaccessible chromatin drive patterning diversification.This article has an associated 'The people behind the papers' interview.
Assuntos
Diferenciação Celular , Cromatina/metabolismo , Desenvolvimento Embrionário , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Neurônios Motores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular , Cromatina/genética , Proteínas de Homeodomínio/genética , Camundongos , Neurônios Motores/citologia , Fatores de Transcrição/genéticaRESUMO
The precision with which motor neurons innervate target muscles depends on a regulatory network of Hox transcription factors that translates neuronal identity into patterns of connectivity. We show that a single transcription factor, FoxP1, coordinates motor neuron subtype identity and connectivity through its activity as a Hox accessory factor. FoxP1 is expressed in Hox-sensitive motor columns and acts as a dose-dependent determinant of columnar fate. Inactivation of Foxp1 abolishes the output of the motor neuron Hox network, reverting the spinal motor system to an ancestral state. The loss of FoxP1 also changes the pattern of motor neuron connectivity, and in the limb motor axons appear to select their trajectories and muscle targets at random. Our findings show that FoxP1 is a crucial determinant of motor neuron diversification and connectivity, and clarify how this Hox regulatory network controls the formation of a topographic neural map.
Assuntos
Diferenciação Celular , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Homeodomínio/metabolismo , Neurônios Motores/metabolismo , Proteínas Repressoras/metabolismo , Medula Espinal/metabolismo , Animais , Embrião de Galinha , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios Motores/citologia , Proteínas Repressoras/genética , Medula Espinal/citologiaRESUMO
Hoxa5 is essential for development of several organs and tissues. In the respiratory system, loss of Hoxa5 function causes neonatal death due to respiratory distress. Expression of HOXA5 protein in mesenchyme of the respiratory tract and in phrenic motor neurons of the central nervous system led us to address the individual contribution of these Hoxa5 expression domains using a conditional gene targeting approach. Hoxa5 does not play a cell-autonomous role in lung epithelium, consistent with lack of HOXA5 expression in this cell layer. In contrast, ablation of Hoxa5 in mesenchyme perturbed trachea development, lung epithelial cell differentiation and lung growth. Further, deletion of Hoxa5 in motor neurons resulted in abnormal diaphragm innervation and musculature, and lung hypoplasia. It also reproduced the neonatal lethality observed in null mutants, indicating that the defective diaphragm is the main cause of impaired survival at birth. Thus, Hoxa5 possesses tissue-specific functions that differentially contribute to the morphogenesis of the respiratory tract.
Assuntos
Proteínas de Homeodomínio/metabolismo , Fosfoproteínas/metabolismo , Sistema Respiratório/embriologia , Sistema Respiratório/metabolismo , Animais , Animais Recém-Nascidos , Padronização Corporal/genética , Cartilagem/embriologia , Cartilagem/metabolismo , Diferenciação Celular/genética , Cruzamentos Genéticos , Diafragma/inervação , Diafragma/metabolismo , Diafragma/ultraestrutura , Feminino , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Proteínas de Homeodomínio/genética , Masculino , Mesoderma/embriologia , Mesoderma/metabolismo , Modelos Biológicos , Neurônios Motores/metabolismo , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/metabolismo , Especificidade de Órgãos/genética , Fosfoproteínas/genética , Mucosa Respiratória/metabolismo , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais/genética , Análise de Sobrevida , Traqueia/embriologia , Traqueia/metabolismo , Fatores de TranscriçãoRESUMO
Polycomb repressive complexes (PRCs) establish and maintain gene repression through chromatin modifications, but their specific roles in cell fate determination events are poorly understood. Here we show an essential role for the PRC1 component Bmi1 in motor neuron (MN) subtype differentiation through dose-dependent effects on Hox gene expression. While Bmi1 is dispensable for generating MNs as a class, it has an essential role in specifying and determining the position of Hox-dependent MN columnar and pool subtypes. These actions are mediated through limiting anterior Hox expression boundaries, functions deployed in post-mitotic MNs, temporally downstream from morphogen gradients. Within the HoxC gene cluster, we found a progressive depletion of PRC-associated marks from rostral to caudal levels of the spinal cord, corresponding to major demarcations of MN subtypes. Selective ablation of Bmi1 elicits a derepression of more posterior Hox genes, leading to a switch in MN fates. Unexpectedly, Hox patterns and MN fates appear to be sensitive to absolute PRC1 activity levels; while reducing Bmi1 switches forelimb lateral motor column (LMC) MNs to a thoracic preganglionic (PGC) identity, elevating Bmi1 expression at thoracic levels converts PGC to LMC MNs. These results suggest that graded PRC1 activities are essential in determining MN topographic organization.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Neurônios Motores/citologia , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Perfilação da Expressão Gênica , Genes Homeobox/genética , Camundongos , Neurônios Motores/metabolismo , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais , Medula Espinal/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismoRESUMO
A critical step in the assembly of the neural circuits that control tetrapod locomotion is the specification of the lateral motor column (LMC), a diverse motor neuron population targeting limb musculature. Hox6 paralog group genes have been implicated as key determinants of LMC fate at forelimb levels of the spinal cord, through their ability to promote expression of the LMC-restricted genes Foxp1 and Raldh2 and to suppress thoracic fates through exclusion of Hoxc9. The specific roles and mechanisms of Hox6 gene function in LMC neurons, however, are not known. We show that Hox6 genes are critical for diverse facets of LMC identity and define motifs required for their in vivo specificities. Although Hox6 genes are necessary for generating the appropriate number of LMC neurons, they are not absolutely required for the induction of forelimb LMC molecular determinants. In the absence of Hox6 activity, LMC identity appears to be preserved through a diverse array of Hox5-Hox8 paralogs, which are sufficient to reprogram thoracic motor neurons to an LMC fate. In contrast to the apparently permissive Hox inputs to early LMC gene programs, individual Hox genes, such as Hoxc6, have specific roles in promoting motor neuron pool diversity within the LMC. Dissection of motifs required for Hox in vivo specificities reveals that either cross-repressive interactions or cooperativity with Pbx cofactors are sufficient to induce LMC identity, with the N-terminus capable of promoting columnar, but not pool, identity when transferred to a heterologous homeodomain. These results indicate that Hox proteins orchestrate diverse aspects of cell fate specification through both the convergent regulation of gene programs regulated by many paralogs and also more restricted actions encoded through specificity determinants in the N-terminus.
Assuntos
Extremidades , Proteínas de Homeodomínio , Neurônios Motores , Medula Espinal , Animais , Diferenciação Celular , Embrião de Galinha , Proteínas de Ligação a DNA/genética , Extremidades/crescimento & desenvolvimento , Extremidades/inervação , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Neurônios Motores/citologia , Neurônios Motores/metabolismo , Mutação , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/metabolismo , Medula Espinal/fisiologiaRESUMO
Hox genes encode transcription factors governing complex developmental processes in several organs. A subset of Hox genes are expressed in the developing lung. Except for Hoxa5, the lack of overt lung phenotype in single mutants suggests that Hox genes may not play a predominant role in lung ontogeny or that functional redundancy may mask anomalies. In the Hox5 paralog group, both Hoxa5 and Hoxb5 genes are expressed in the lung mesenchyme whereas Hoxa5 is also expressed in the tracheal mesenchyme. Herein, we generated Hoxa5;Hoxb5 compound mutant mice to evaluate the relative contribution of each gene to lung development. Hoxa5;Hoxb5 mutants carrying the four mutated alleles displayed an aggravated lung phenotype, resulting in the death of the mutant pups at birth. Characterization of the phenotype highlighted the role of Hoxb5 in lung formation, the latter being involved in branching morphogenesis, goblet cell specification, and postnatal air space structure, revealing partial functional redundancy with Hoxa5. However, the Hoxb5 lung phenotypes were less severe than those seen in Hoxa5 mutants, likely because of Hoxa5 compensation. New specific roles for Hoxa5 were also unveiled, demonstrating the extensive contribution of Hoxa5 to the developing respiratory system. The exclusive expression of Hoxa5 in the trachea and the phrenic motor column likely underlies the Hoxa5-specific trachea and diaphragm phenotypes. Altogether, our observations establish that the Hoxa5 and Hoxb5 paralog genes shared some functions during lung morphogenesis, Hoxa5 playing a predominant role.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Pulmão/metabolismo , Morfogênese/genética , Fosfoproteínas/genética , Animais , Diafragma/embriologia , Diafragma/metabolismo , Embrião de Mamíferos , Feminino , Células Caliciformes/metabolismo , Heterozigoto , Proteínas de Homeodomínio/metabolismo , Homozigoto , Pulmão/embriologia , Masculino , Camundongos , Camundongos Transgênicos , Fosfoproteínas/metabolismo , Nervo Frênico/embriologia , Nervo Frênico/metabolismo , Traqueia/embriologia , Traqueia/metabolismo , Fatores de TranscriçãoRESUMO
Locomotion requires precise control of the strength and speed of muscle contraction and is achieved by recruiting functionally distinct subtypes of motor neurons (MNs). MNs are essential to movement and differentially susceptible in disease, but little is known about how MNs acquire functional subtype-specific features during development. Using single-cell RNA profiling in embryonic and larval zebrafish, we identify novel and conserved molecular signatures for MN functional subtypes and identify genes expressed in both early post-mitotic and mature MNs. Assessing MN development in genetic mutants, we define a molecular program essential for MN functional subtype specification. Two evolutionarily conserved transcription factors, Prdm16 and Mecom, are both functional subtype-specific determinants integral for fast MN development. Loss of prdm16 or mecom causes fast MNs to develop transcriptional profiles and innervation similar to slow MNs. These results reveal the molecular diversity of vertebrate axial MNs and demonstrate that functional subtypes are specified through intrinsic transcriptional codes.
Assuntos
Medula Espinal , Peixe-Zebra , Animais , Neurônios Motores/fisiologia , Fatores de Transcrição/genética , LocomoçãoRESUMO
Spinal motoneurons are a remarkably diverse class of neurons responsible for facilitating a broad range of motor behaviors and autonomic functions. Studies of motoneuron differentiation have provided fundamental insights into the developmental mechanisms of neuronal diversification, and have illuminated principles of neural fate specification that operate throughout the central nervous system. Because of their relative anatomical simplicity and accessibility, motoneurons have provided a tractable model system to address multiple facets of neural development, including early patterning, neuronal migration, axon guidance, and synaptic specificity. Beyond their roles in providing direct communication between central circuits and muscle, recent studies have revealed that motoneuron subtype-specific programs also play important roles in determining the central connectivity and function of motor circuits. Cross-species comparative analyses have provided novel insights into how evolutionary changes in subtype specification programs may have contributed to adaptive changes in locomotor behaviors. This chapter focusses on the gene regulatory networks governing spinal motoneuron specification, and how studies of spinal motoneurons have informed our understanding of the basic mechanisms of neuronal specification and spinal circuit assembly.
Assuntos
Neurônios Motores , Medula Espinal , Humanos , Músculos , NeurogêneseRESUMO
Polycomb repressive complexes (PRCs) 1 and 2 maintain stable cellular memories of early fate decisions by establishing heritable patterns of gene repression. PRCs repress transcription through histone modifications and chromatin compaction, but their roles in neuronal subtype diversification are poorly defined. We found that PRC1 is essential for the specification of segmentally restricted spinal motor neuron (MN) subtypes, while PRC2 activity is dispensable to maintain MN positional identities during terminal differentiation. Mutation of the core PRC1 component Ring1 in mice leads to increased chromatin accessibility and ectopic expression of a broad variety of fates determinants, including Hox transcription factors, while neuronal class-specific features are maintained. Loss of MN subtype identities in Ring1 mutants is due to the suppression of Hox-dependent specification programs by derepressed Hox13 paralogs (Hoxa13, Hoxb13, Hoxc13, Hoxd13). These results indicate that PRC1 can function in the absence of de novo PRC2-dependent histone methylation to maintain chromatin topology and postmitotic neuronal fate.
Assuntos
Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Neurônios Motores/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 2/genética , Animais , Animais Geneticamente Modificados , Galinhas , Camundongos , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 2/metabolismoRESUMO
The little skate Leucoraja erinacea, a cartilaginous fish, displays pelvic fin driven walking-like behavior using genetic programs and neuronal subtypes similar to those of land vertebrates. However, mechanistic studies on little skate motor circuit development have been limited, due to a lack of high-quality reference genome. Here, we generated an assembly of the little skate genome, with precise gene annotation and structures, which allowed post-genome analysis of spinal motor neurons (MNs) essential for locomotion. Through interspecies comparison of mouse, skate and chicken MN transcriptomes, shared and divergent gene expression profiles were identified. Comparison of accessible chromatin regions between mouse and skate MNs predicted shared transcription factor (TF) motifs with divergent ones, which could be used for achieving differential regulation of MN-expressed genes. A greater number of TF motif predictions were observed in MN-expressed genes in mouse than in little skate. These findings suggest conserved and divergent molecular mechanisms controlling MN development of vertebrates during evolution, which might contribute to intricate gene regulatory networks in the emergence of a more sophisticated motor system in tetrapods.
Assuntos
Rajidae , Animais , Camundongos , Cromatina/metabolismo , Neurônios Motores , Rajidae/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Caminhada , GenomaRESUMO
The control of movement relies on the precision with which motor circuits are assembled during development. Spinal motor neurons (MNs) provide the trigger to signal the appropriate sequence of muscle contractions and initiate movement. This task is accommodated by the diversification of MNs into discrete subpopulations, each of which acquires precise axonal trajectories and central connectivity patterns. An upstream Hox factor-based regulatory network in MNs defines their competence to deploy downstream programs including the expression of Nkx and ETS transcription factors. These interactive transcriptional programs coordinate MN differentiation and connectivity, defining a sophisticated roadmap of motor circuit assembly in the spinal cord. Similar principles using modular interaction of transcriptional programs to control neuronal diversification and circuit connectivity are likely to act in other CNS circuits.
Assuntos
Neurônios Motores/metabolismo , Medula Espinal/embriologia , Medula Espinal/metabolismo , Fatores de Transcrição/genética , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Vias Eferentes/citologia , Vias Eferentes/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Homeodomínio/genética , Humanos , Neurônios Motores/citologia , Músculo Esquelético/embriologia , Músculo Esquelético/inervação , Medula Espinal/citologia , Ativação Transcricional/genéticaRESUMO
The organization of neurons into columns is a prominent feature of central nervous system structure and function. In many regions of the central nervous system the grouping of neurons into columns links cell-body position to axonal trajectory, thus contributing to the establishment of topographic neural maps. This link is prominent in the developing spinal cord, where columnar sets of motor neurons innervate distinct targets in the periphery. We show here that sequential phases of Hox-c protein expression and activity control the columnar differentiation of spinal motor neurons. Hox expression in neural progenitors is established by graded fibroblast growth factor signalling and translated into a distinct motor neuron Hox pattern. Motor neuron columnar fate then emerges through cell autonomous repressor and activator functions of Hox proteins. Hox proteins also direct the expression of genes that establish motor topographic projections, thus implicating Hox proteins as critical determinants of spinal motor neuron identity and organization.
Assuntos
Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Neurônios Motores/citologia , Neurônios Motores/metabolismo , Medula Espinal/citologia , Medula Espinal/metabolismo , Animais , Padronização Corporal/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Embrião de Galinha , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fator 8 de Crescimento de Fibroblasto , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Camundongos , Mitose , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/embriologia , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismoRESUMO
Coordinated motor behaviors depend on feedback communication between peripheral sensory systems and central circuits in the brain and spinal cord. Relay of muscle- and tendon-derived sensory information to the CNS is facilitated by functionally and anatomically diverse groups of spinocerebellar tract neurons (SCTNs), but the molecular logic by which SCTN diversity and connectivity is achieved is poorly understood. We used single-cell RNA sequencing and genetic manipulations to define the mechanisms governing the molecular profile and organization of SCTN subtypes. We found that SCTNs relaying proprioceptive sensory information from limb and axial muscles are generated through segmentally restricted actions of specific Hox genes. Loss of Hox function disrupts SCTN-subtype-specific transcriptional programs, leading to defects in the connections between proprioceptive sensory neurons, SCTNs, and the cerebellum. These results indicate that Hox-dependent genetic programs play essential roles in the assembly of neural circuits necessary for communication between the brain and spinal cord.
Assuntos
Proteínas de Homeodomínio/fisiologia , Neurônios Motores/fisiologia , Rede Nervosa/fisiologia , Células Receptoras Sensoriais/fisiologia , Tratos Espinocerebelares/fisiologia , Animais , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos Knockout , Neurônios Motores/citologia , Células Receptoras Sensoriais/citologia , Tratos Espinocerebelares/citologiaRESUMO
Nervous systems control locomotion using rhythmically active networks that orchestrate motor neuron firing patterns. Whether animals use common or distinct genetic programs to encode motor rhythmicity remains unclear. Cross-species comparisons have revealed remarkably conserved neural patterning systems but have also unveiled divergent circuit architectures that can generate similar locomotor behaviors.
Assuntos
Comportamento Animal/fisiologia , Locomoção/fisiologia , Neurônios Motores/fisiologia , Periodicidade , Medula Espinal/crescimento & desenvolvimento , Animais , Medula Espinal/fisiologiaRESUMO
Neuronal control of muscles associated with the central body axis is an ancient and essential function of the nervous systems of most animal species. Throughout the course of vertebrate evolution, motor circuits dedicated to control of axial muscle have undergone significant changes in their roles within the motor system. In most fish species, axial circuits are critical for coordinating muscle activation sequences essential for locomotion and play important roles in postural correction. In tetrapods, axial circuits have evolved unique functions essential to terrestrial life, including maintaining spinal alignment and breathing. Despite the diverse roles of axial neural circuits in motor behaviors, the genetic programs underlying their assembly are poorly understood. In this review, we describe recent studies that have shed light on the development of axial motor circuits and compare and contrast the strategies used to wire these neural networks in aquatic and terrestrial vertebrate species.