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Establishing and maintaining Hox profiles during spinal cord development

Miller, Alexander; Dasen, Jeremy S
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.
PMCID:10524138
PMID: 37029058
ISSN: 1096-3634
CID: 5625672

SorCS2 binds progranulin to regulate motor neuron development

Thomasen, Pernille Bogetofte; Salasova, Alena; Kjaer-Sorensen, Kasper; Woloszczuková, Lucie; Lavický, Josef; Login, Hande; Tranberg-Jensen, Jeppe; Almeida, Sergio; Beel, Sander; Kavková, Michaela; Qvist, Per; Kjolby, Mads; Ovesen, Peter Lund; Nolte, Stella; Vestergaard, Benedicte; Udrea, Andreea-Cornelia; Nejsum, Lene Niemann; Chao, Moses V; Van Damme, Philip; Krivanek, Jan; Dasen, Jeremy; Oxvig, Claus; Nykjaer, Anders
Motor neuron (MN) development and nerve regeneration requires orchestrated action of a vast number of molecules. Here, we identify SorCS2 as a progranulin (PGRN) receptor that is required for MN diversification and axon outgrowth in zebrafish and mice. In zebrafish, SorCS2 knockdown also affects neuromuscular junction morphology and fish motility. In mice, SorCS2 and PGRN are co-expressed by newborn MNs from embryonic day 9.5 until adulthood. Using cell-fate tracing and nerve segmentation, we find that SorCS2 deficiency perturbs cell-fate decisions of brachial MNs accompanied by innervation deficits of posterior nerves. Additionally, adult SorCS2 knockout mice display slower motor nerve regeneration. Interestingly, primitive macrophages express high levels of PGRN, and their interaction with SorCS2-positive motor axon is required during axon pathfinding. We further show that SorCS2 binds PGRN to control its secretion, signaling, and conversion into granulins. We propose that PGRN-SorCS2 signaling controls MN development and regeneration in vertebrates.
PMID: 37897724
ISSN: 2211-1247
CID: 5590282

Determinants of motor neuron functional subtypes important for locomotor speed

D'Elia, Kristen P; Hameedy, Hanna; Goldblatt, Dena; Frazel, Paul; Kriese, Mercer; Zhu, Yunlu; Hamling, Kyla R; Kawakami, Koichi; Liddelow, Shane A; Schoppik, David; Dasen, Jeremy S
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.
PMCID:10600875
PMID: 37676768
ISSN: 2211-1247
CID: 5607632

Establishing and maintaining Hox profiles during spinal cord development

Miller, Alexander; Dasen, Jeremy S.
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.
SCOPUS:85151712643
ISSN: 1084-9521
CID: 5460542

Little skate genome provides insights into genetic programs essential for limb-based locomotion

Yoo, DongAhn; Park, Junhee; Lee, Chul; Song, Injun; Lee, Young Ho; Yun, Tery; Lee, Hyemin; Heguy, Adriana; Han, Jae Yong; Dasen, Jeremy S; Kim, Heebal; Baek, Myungin
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.
PMCID:9605692
PMID: 36288084
ISSN: 2050-084x
CID: 5358042

PRC1 sustains the integrity of neural fate in the absence of PRC2 function

Sawai, Ayana; Pfennig, Sarah; Bulajić, Milica; Miller, Alexander; Khodadadi-Jamayran, Alireza; Mazzoni, Esteban Orlando; Dasen, Jeremy S
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.
PMID: 34994686
ISSN: 2050-084x
CID: 5107472

Big insight from the little skate: Leucoraja erinacea as a developmental model system

Gillis, J Andrew; Bennett, Scott; Criswell, Katharine E; Rees, Jenaid; Sleight, Victoria A; Hirschberger, Christine; Calzarette, Dan; Kerr, Sarah; Dasen, Jeremy
The vast majority of extant vertebrate diversity lies within the bony and cartilaginous fish lineages of jawed vertebrates. There is a long history of elegant experimental investigation of development in bony vertebrate model systems (e.g., mouse, chick, frog and zebrafish). However, studies on the development of cartilaginous fishes (sharks, skates and rays) have, until recently, been largely descriptive, owing to the challenges of embryonic manipulation and culture in this group. This, in turn, has hindered understanding of the evolution of developmental mechanisms within cartilaginous fishes and, more broadly, within jawed vertebrates. The little skate (Leucoraja erinacea) is an oviparous cartilaginous fish and has emerged as a powerful and experimentally tractable developmental model system. Here, we discuss the collection, husbandry and management of little skate brood stock and eggs, and we present an overview of key stages of skate embryonic development. We also discuss methods for the manipulation and culture of skate embryos and illustrate the range of tools and approaches available for studying this system. Finally, we summarize a selection of recent studies on skate development that highlight the utility of this system for inferring ancestral anatomical and developmental conditions for jawed vertebrates, as well as unique aspects of cartilaginous fish biology.
PMID: 35337464
ISSN: 1557-8933
CID: 5190652

Establishing the Molecular and Functional Diversity of Spinal Motoneurons

Dasen, Jeremy S
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.
PMID: 36066819
ISSN: 2190-5215
CID: 5332402

Differential abilities to engage inaccessible chromatin diversify vertebrate HOX binding patterns

Bulajić, Milica; Srivastava, Divyanshi; Dasen, Jeremy S; Wichterle, Hynek; Mahony, Shaun; Mazzoni, Esteban O
While 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 aim 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 find 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 are explained by differing abilities to bind to previously inaccessible sites. For example, the posterior group HOXC9 has 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.
PMID: 33028607
ISSN: 1477-9129
CID: 4627022

Intrinsic control of neuronal diversity and synaptic specificity in a proprioceptive circuit

Shin, Maggie M; Catela, Catarina; Dasen, Jeremy
Relay of muscle-derived sensory information to the CNS is essential for the execution of motor behavior, but how proprioceptive sensory neurons (pSNs) establish functionally appropriate connections is poorly understood. A prevailing model of sensory-motor circuit assembly is that peripheral, target-derived, cues instruct pSN identities and patterns of intraspinal connectivity. To date no known intrinsic determinants of muscle-specific pSN fates have been described in vertebrates. We show that expression of Hox transcription factors defines pSN subtypes, and these profiles are established independently of limb muscle. The Hoxc8 gene is expressed by pSNs and motor neurons (MNs) targeting distal forelimb muscles, and sensory-specific depletion of Hoxc8 in mice disrupts sensory-motor synaptic matching, without affecting pSN survival or muscle targeting. These results indicate that the diversity and central specificity of pSNs and MNs are regulated by a common set of determinants, thus linking early rostrocaudal patterning to the assembly of limb control circuits.
PMCID:7467731
PMID: 32808924
ISSN: 2050-084x
CID: 4590142