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Crossing the Midline: Locomotor Neuronal Circuitry Formation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Developmental genetics)
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Networks at various levels of the nervous system coordinate different motor patterns such as respiration, eye or hand movements and locomotion. Intrinsic rhythm-generating networks that are located in the spinal cord generate motor behaviors that underlie locomotion in vertebrates. These networks give a continuous and measurable coordinated rhythmic motor output and are referred to as locomotor central pattern generators (CPGs). Characterization of the mammalian locomotor CPG and its molecular control is depending on the identification of participating neurons and neuronal populations. In this thesis I present work where we have studied the significance of subpopulations of neurons in the formation and function of the left-right circuitry. In summary, we show that the axon guidance receptor DCC has a central role in the formation of spinal neuronal circuitry underlying left-right coordination, and that both Netrin-1 and DCC are required for normal function of the locomotor CPG. Commissural interneurons (CINs), which send their axons across the ventral midline in the spinal cord, play a critical role in left–right coordination during locomotion. A complete loss of commissural axons in the spinal cord, as seen in the Robo3 null mutant mouse, resulted in uncoordinated fictional locomotor activity. Removing CIN connections from either dorsal or ventral neuronal populations led to a shift from alternation to strict synchronous locomotor activity. Inhibitory dI6 CIN have been suggested as promising candidate neurons in coordinating bilateral alternation circuitry. We have identified that Dmrt3, expressed in inhibitory dI6 CINs, is a crucial component for the normal development of coordinated locomotor movements in both horses and mice. We have also concluded that the prominent hopping phenotype seen in hop/hop mice is a result of abnormal developmental processes including induction from the notochord and Shh signaling. Together, these findings increase our knowledge about the flexibility in neuronal circuit development and further confirm the role of dI6 neurons in locomotor circuits.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 43 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 825
Keyword [en]
CPG, CIN, neuronal network, locomotion, left-right alternation
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-182692ISBN: 978-91-554-8500-9 (print)OAI: oai:DiVA.org:uu-182692DiVA: diva2:560553
Public defence
2012-12-01, B22 BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-11-08 Created: 2012-10-15 Last updated: 2013-01-23
List of papers
1. Netrin-1-Dependent Spinal Interneuron Subtypes Are Required for the Formation of Left-Right Alternating Locomotor Circuitry
Open this publication in new window or tab >>Netrin-1-Dependent Spinal Interneuron Subtypes Are Required for the Formation of Left-Right Alternating Locomotor Circuitry
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2009 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 50, 15642-15649 p.Article in journal (Refereed) Published
Abstract [en]

Neuronal circuits in the spinal cord that produce the rhythmic and coordinated activities necessary for limb movements are referred to as locomotor central pattern generators (CPGs). The identities and preceding development of neurons essential for coordination between left and right limbs are not yet known. We show that the ventral floor plate chemoattractant Netrin-1 preferentially guides dorsally originating subtypes of commissural interneurons, the majority of which are inhibitory. In contrast, the excitatory and ventralmost V3 subtype of interneurons have a normal number of commissural fibers in Netrin-1 mutant mice, thus being entirely independent of Netrin-1-mediated attraction. This selective loss of commissural fibers in Netrin-1 mutant mice resulted in an abnormal circuitry manifested by a complete switch from alternating to synchronous fictive locomotor activity suggesting that the most ventral-originating excitatory commissural interneurons are an important component of a left-right synchrony circuit in the locomotor CPG. Thus, during development, Netrin-1 plays a critical role for the establishment of a functional balanced CPG.

Keyword
neuronal network, development, central pattern generator, commissural interneuron subtypes
National Category
Medical and Health Sciences
Research subject
Developmental Neurosciences
Identifiers
urn:nbn:se:uu:diva-112466 (URN)10.1523/JNEUROSCI.5096-09.2009 (DOI)000272837000004 ()
Available from: 2010-01-13 Created: 2010-01-13 Last updated: 2017-12-12Bibliographically approved
2. DCC mediated axon guidance of spinal interneurons is essential for normal locomotor central pattern generator function
Open this publication in new window or tab >>DCC mediated axon guidance of spinal interneurons is essential for normal locomotor central pattern generator function
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2012 (English)In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 366, no 2, 279-289 p.Article in journal (Refereed) Published
Abstract [en]

Coordinated limb rhythmic movements take place through organized signaling in local spinal cord neuronal networks. The establishment of these circuitries during development is dependent on the correct guidance of axons to their targets. It has previously been shown that the well-known axon guidance molecule netrin-1 is required for configuring the circuitry that provides left-right alternating coordination in fictive locomotion. The attraction of commissural axons to the midline in response to netrin-1 has been shown to involve the netrin-1 receptor DCC (deleted in Colorectal Cancer). However, the role of DCC for the establishment of CPG coordination has not yet been resolved. We show that mice carrying a null mutation of DCC displayed an uncoordinated left-right activity during fictive locomotion accompanied by a loss of interneuronal subpopulations originating from commissural progenitors. Thus, DCC plays a crucial role in the formation of spinal neuronal circuitry coordinating left-right activities. Together with the previously published results from netrin-1 deficient mice, the data presented in this study suggest a role for the most ventral originating V3 interneurons in synchronous activities over the midline. Further, it provides evidence that axon crossing in the spinal cord is more intricately controlled than in previously suggested models of DCC-netrin-1 interaction.

Keyword
Neuronal network, Commissural interneuron, V3 subtype, Development, Axon guidance
National Category
Neurosciences
Research subject
Developmental Neurosciences
Identifiers
urn:nbn:se:uu:diva-112468 (URN)10.1016/j.ydbio.2012.03.017 (DOI)000304788600016 ()
Note
Manuscript original title: Netrin-1-independent DCC mediated axonguidance of V3 interneurons forms a CPG synchrony circuitAvailable from: 2010-01-13 Created: 2010-01-13 Last updated: 2017-12-12Bibliographically approved
3. The role of Robo3 subpopulations in the spinal locomotor CPG
Open this publication in new window or tab >>The role of Robo3 subpopulations in the spinal locomotor CPG
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-182632 (URN)
Available from: 2012-10-13 Created: 2012-10-13 Last updated: 2012-11-12
4. Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice
Open this publication in new window or tab >>Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice
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2012 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 488, no 7413, 642-646 p.Article in journal (Refereed) Published
Abstract [en]

Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement(1). These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles(2). Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-181404 (URN)10.1038/nature11399 (DOI)000308095100053 ()
Available from: 2012-09-28 Created: 2012-09-24 Last updated: 2017-12-07Bibliographically approved
5. The hop mutation causes a restricted merge of the ventral lumbarspinal cord resulting in fused CPG half-centers and synchronoushind-limb gait
Open this publication in new window or tab >>The hop mutation causes a restricted merge of the ventral lumbarspinal cord resulting in fused CPG half-centers and synchronoushind-limb gait
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-182633 (URN)
Available from: 2012-10-13 Created: 2012-10-13 Last updated: 2012-11-12

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