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DCC mediated axon guidance of spinal interneurons is essential for normal locomotor central pattern generator function
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. (Formation and function of neuronal circuits)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. (Formation and function of neuronal circuits)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. (Formation and function of neuronal circuits)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. (Formation and function of neuronal circuits)
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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.

Place, publisher, year, edition, pages
2012. Vol. 366, no 2, 279-289 p.
Keyword [en]
Neuronal network, Commissural interneuron, V3 subtype, Development, Axon guidance
National Category
Neurosciences
Research subject
Developmental Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-112468DOI: 10.1016/j.ydbio.2012.03.017ISI: 000304788600016OAI: oai:DiVA.org:uu-112468DiVA: diva2:286122
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
In thesis
1. Spinal Control of Locomotion: Developmental and Functional Aspects
Open this publication in new window or tab >>Spinal Control of Locomotion: Developmental and Functional Aspects
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuronal networks are the central functional units of the nervous system. Knowledge about the identity of participating neurons and the assembly of these during development is crucial for the understanding of CNS function. A promising system to dissect the development and functionalities of a neuronal network is the central pattern generator (CPG) for locomotion. We used screening approaches to identify spinal neuronal subpopulations by their specific gene expression, potentially involved in CPG function. Amongst others we found paired-like homeodomain transcription factor 2 (Pitx2) as a cholinergic interneuron marker for partition cells, with a possible role in the spinal network for locomotion. In addition, we present two genes, Chondrolectin (Chodl) and Estrogen-related receptor beta (ERRβ) as novel markers for fast and slow motor neurons, respectively.

The neuronal components of the CPG integrate three key functions; rhythm generation, ipsilateral flexors/extensors coordination and bilateral coordination over the midline. Commissural interneurons (CINs) are considered to participate in the latter. During development axons are guided to their targets by the help of axon guidance molecules. Netrin-1 and its receptor DCC (Deleted in Colorectal Cancer) have been shown to play an important role for spinal cord neurons in axon-pathfinding and migration towards the midline. We show that loss of netrin-1 functionally results in a switch from alternating to synchronous left-right locomotor activity and deletion of DCC surprisingly leads to a different phenotype, best described as uncoordination. Thus, during development, netrin-1 and DCC play a critical role for the establishment of a functional balanced CPG. Further we show a selective loss of CINs, predominantly from dorsally originating subtypes, not affecting the ventral-most V3 subtype in netrin-1 mutant mice, but a loss of CINs from all progenitor domains in Dcc mutant mice. Together, our data suggest a netrin-1-independent mechanism for DCC in axon guidance and a role of the most ventral originating CINs as part of the neuronal network controlling synchronous activities over the midline.

Another pair of axon guidance molecules, EphA4 and ephrinB3, has been shown to cooperate in preventing ipsilateral interneurons from crossing the spinal midline and if either molecule is deleted in mice, this will result in a defect in left-right coordination of locomotion. We provide in vivo and in vitro evidence that the GTPase-activating protein α2-chimerin, as a downstream molecule of EphA4 signaling, is essential in axon guidance decisions involved in the correct formation of the spinal circuitry for locomotion.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 40 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 514
Keyword
neuronal network, commissural interneuron, developmental interneuron subtypes, V3, mouse genetics, Pitx2, axon guidance, netrin-1, DCC, EphA4
National Category
Neurosciences
Research subject
Neuroscience; Developmental Neurosciences; Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-112472 (URN)978-91-554-7704-2 (ISBN)
Public defence
2010-02-26, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2010-02-05 Created: 2010-01-13 Last updated: 2010-02-05Bibliographically approved
2. Crossing the Midline: Locomotor Neuronal Circuitry Formation
Open this publication in new window or tab >>Crossing the Midline: Locomotor Neuronal Circuitry Formation
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
CPG, CIN, neuronal network, locomotion, left-right alternation
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-182692 (URN)978-91-554-8500-9 (ISBN)
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

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Rabe Bernhardt, NadineMemic, FatimaGezelius, HenrikKullander, Klas

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