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Topographic Maps: Motor Axons Wait Their Turn

D'Elia, Kristen P; Dasen, Jeremy S
Topographic maps are a basic organizational feature of nervous systems, and their construction involves both spatial and temporal cues. A recent study reports a novel mechanism of topographic map formation which relies on the timing of axon initiation.
PMID: 29374453
ISSN: 1879-0445
CID: 2929102

Origin and Segmental Diversity of Spinal Inhibitory Interneurons

Sweeney, Lora B; Bikoff, Jay B; Gabitto, Mariano I; Brenner-Morton, Susan; Baek, Myungin; Yang, Jerry H; Tabak, Esteban G; Dasen, Jeremy S; Kintner, Christopher R; Jessell, Thomas M
Motor output varies along the rostro-caudal axis of the tetrapod spinal cord. At limb levels, ∼60 motor pools control the alternation of flexor and extensor muscles about each joint, whereas at thoracic levels as few as 10 motor pools supply muscle groups that support posture, inspiration, and expiration. Whether such differences in motor neuron identity and muscle number are associated with segmental distinctions in interneuron diversity has not been resolved. We show that select combinations of nineteen transcription factors that specify lumbar V1 inhibitory interneurons generate subpopulations enriched at limb and thoracic levels. Specification of limb and thoracic V1 interneurons involves the Hox gene Hoxc9 independently of motor neurons. Thus, early Hox patterning of the spinal cord determines the identity of V1 interneurons and motor neurons. These studies reveal a developmental program of V1 interneuron diversity, providing insight into the organization of inhibitory interneurons associated with differential motor output.
PMID: 29307712
ISSN: 1097-4199
CID: 2906602

HOXA5 plays tissue-specific roles in the developing respiratory system

Landry-Truchon, Kim; Houde, Nicolas; Boucherat, Olivier; Joncas, France-Helene; Dasen, Jeremy S; Philippidou, Polyxeni; Mansfield, Jennifer H; Jeannotte, Lucie
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 with 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.
PMID: 28827394
ISSN: 1477-9129
CID: 2676672

Divergent Hox Coding and Evasion of Retinoid Signaling Specifies Motor Neurons Innervating Digit Muscles

Mendelsohn, Alana I; Dasen, Jeremy S; Jessell, Thomas M
The establishment of spinal motor neuron subclass diversity is achieved through developmental programs that are aligned with the organization of muscle targets in the limb. The evolutionary emergence of digits represents a specialized adaptation of limb morphology, yet it remains unclear how the specification of digit-innervating motor neuron subtypes parallels the elaboration of digits. We show that digit-innervating motor neurons can be defined by selective gene markers and distinguished from other LMC neurons by the expression of a variant Hox gene repertoire and by the failure to express a key enzyme involved in retinoic acid synthesis. This divergent developmental program is sufficient to induce the specification of digit-innervating motor neurons, emphasizing the specialized status of digit control in the evolution of skilled motor behaviors. Our findings suggest that the emergence of digits in the limb is matched by distinct mechanisms for specifying motor neurons that innervate digit muscles.
PMID: 28190640
ISSN: 1097-4199
CID: 2449032

Master or servant? emerging roles for motor neuron subtypes in the construction and evolution of locomotor circuits

Dasen, Jeremy S
Execution of motor behaviors relies on the ability of circuits within the nervous system to engage functionally relevant subtypes of spinal motor neurons. While much attention has been given to the role of networks of spinal interneurons on setting the rhythm and pattern of output from locomotor circuits, recent studies suggest that motor neurons themselves can exert an instructive role in shaping the wiring and functional properties of locomotor networks. Alteration in the distribution of motor neuron subtypes also appears to have contributed to evolutionary transitions in the locomotor strategies used by land vertebrates. This review describes emerging evidence that motor neuron-derived cues can have a profound influence on the organization, wiring, and evolutionary diversification of locomotor circuits.
PMID: 27907815
ISSN: 1873-6882
CID: 2329422

A viral strategy for targeting and manipulating interneurons across vertebrate species

Dimidschstein, Jordane; Chen, Qian; Tremblay, Robin; Rogers, Stephanie L; Saldi, Giuseppe-Antonio; Guo, Lihua; Xu, Qing; Liu, Runpeng; Lu, Congyi; Chu, Jianhua; Avery, Michael C; Rashid, Mohammad S; Baek, Myungin; Jacob, Amanda L; Smith, Gordon B; Wilson, Daniel E; Kosche, Georg; Kruglikov, Illya; Rusielewicz, Tomasz; Kotak, Vibhakar C; Mowery, Todd M; Anderson, Stewart A; Callaway, Edward M; Dasen, Jeremy S; Fitzpatrick, David; Fossati, Valentina; Long, Michael A; Noggle, Scott; Reynolds, John H; Sanes, Dan H; Rudy, Bernardo; Feng, Guoping; Fishell, Gord
A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations. The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types. In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans. Here we describe a novel recombinant adeno-associated virus that restricts gene expression to GABAergic interneurons within the telencephalon. We demonstrate that the viral expression is specific and robust, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in both mice and non-genetically tractable species, thus opening the possibility to study GABAergic function in virtually any vertebrate species.
PMID: 27798629
ISSN: 1546-1726
CID: 2297132

Parallel Pbx-Dependent Pathways Govern the Coalescence and Fate of Motor Columns

Hanley, Olivia; Zewdu, Rediet; Cohen, Lisa J; Jung, Heekyung; Lacombe, Julie; Philippidou, Polyxeni; Lee, David H; Selleri, Licia; Dasen, Jeremy S
The clustering of neurons sharing similar functional properties and connectivity is a common organizational feature of vertebrate nervous systems. Within motor networks, spinal motor neurons (MNs) segregate into longitudinally arrayed subtypes, establishing a central somatotopic map of peripheral target innervation. MN organization and connectivity relies on Hox transcription factors expressed along the rostrocaudal axis; however, the developmental mechanisms governing the orderly arrangement of MNs are largely unknown. We show that Pbx genes, which encode Hox cofactors, are essential for the segregation and clustering of neurons within motor columns. In the absence of Pbx1 and Pbx3 function, Hox-dependent programs are lost and the remaining MN subtypes are unclustered and disordered. Identification of Pbx gene targets revealed an unexpected and apparently Hox-independent role in defining molecular features of dorsally projecting medial motor column (MMC) neurons. These results indicate Pbx genes act in parallel genetic pathways to orchestrate neuronal subtype differentiation, connectivity, and organization.
PMID: 27568519
ISSN: 1097-4199
CID: 2232352

Hox Proteins Coordinate Motor Neuron Differentiation and Connectivity Programs through Ret/Gfralpha Genes

Catela, Catarina; Shin, Maggie M; Lee, David H; Liu, Jeh-Ping; Dasen, Jeremy S
The accuracy of neural circuit assembly relies on the precise spatial and temporal control of synaptic specificity determinants during development. Hox transcription factors govern key aspects of motor neuron (MN) differentiation; however, the terminal effectors of their actions are largely unknown. We show that Hox/Hox cofactor interactions coordinate MN subtype diversification and connectivity through Ret/Gfralpha receptor genes. Hox and Meis proteins determine the levels of Ret in MNs and define the intrasegmental profiles of Gfralpha1 and Gfralpha3 expression. Loss of Ret or Gfralpha3 leads to MN specification and innervation defects similar to those observed in Hox mutants, while expression of Ret and Gfralpha1 can bypass the requirement for Hox genes during MN pool differentiation. These studies indicate that Hox proteins contribute to neuronal fate and muscle connectivity through controlling the levels and pattern of cell surface receptor expression, consequently gating the ability of MNs to respond to limb-derived instructive cues.
PMID: 26904955
ISSN: 2211-1247
CID: 1965412

Sensory-Motor Circuits: Hox Genes Get in Touch

Philippidou, Polyxeni; Dasen, Jeremy S
Sensory-motor reflex circuits are the basic units from which animal nervous systems are constructed, yet little is known regarding how connections within these simple networks are established. In papers in Cell Reports and in this issue of Neuron, Zheng et al. (2015a, 2015b) demonstrate that coordinate activities of Hox genes in sensory neurons and interneurons govern connectivity within touch-reflex circuits in C. elegans.
PMID: 26539884
ISSN: 1097-4199
CID: 1825962

Evolution of Patterning Systems and Circuit Elements for Locomotion

Jung, Heekyung; Dasen, Jeremy S
Evolutionary modifications in nervous systems enabled organisms to adapt to their specific environments and underlie the remarkable diversity of behaviors expressed by animals. Resolving the pathways that shaped and modified neural circuits during evolution remains a significant challenge. Comparative studies have revealed a surprising conservation in the intrinsic signaling systems involved in early patterning of bilaterian nervous systems but also raise the question of how neural circuit compositions and architectures evolved within specific animal lineages. In this review, we argue that within the spinal cord a flexible system involving modulation of rostrocaudal positional information, acting in the context of a relatively uniform DV patterning system, can act to modify neuronal organization and connectivity within circuits governing a specific locomotor output.
PMID: 25710528
ISSN: 1534-5807
CID: 1473712