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Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
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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.

Place, publisher, year, edition, pages
2012. Vol. 488, no 7413, 642-646 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-181404DOI: 10.1038/nature11399ISI: 000308095100053OAI: oai:DiVA.org:uu-181404DiVA: diva2:557676
Available from: 2012-09-28 Created: 2012-09-24 Last updated: 2017-12-07Bibliographically approved
In thesis
1. 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
2. Neuronal Networks of Movement: Slc10a4 as a Modulator & Dmrt3 as a Gait-keeper
Open this publication in new window or tab >>Neuronal Networks of Movement: Slc10a4 as a Modulator & Dmrt3 as a Gait-keeper
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nerve cells are organized into complex networks that comprise the building blocks of our nervous system. Neurons communicate by transmitting messenger molecules released from synaptic vesicles. Alterations in neuronal circuitry and synaptic signaling contribute to a wide range of neurological conditions, often with consequences for movement. Intrinsic neuronal networks in the spinal cord serve to coordinate vital rhythmic motor functions. In spite of extensive efforts to address the organization of these neural circuits, much remains to be revealed regarding the identity and function of specific interneuron cell types and how neuromodulation tune network activity. In this thesis, two novel genes initially identified as markers for spinal neuronal populations were investigated: Slc10a4 and Dmrt3.

The orphan transporter SLC10A4 was found to be expressed on synaptic vesicles of the cholinergic system, including motor neurons, as well as in the monoaminergic system, including dopaminergic, serotonergic and noradrenergic nuclei. Thus, it constitutes a novel molecular denominator shared by these classic neuromodulatory systems. SLC10A4 was found to influence vesicular transport of dopamine and affect neuronal release and reuptake efficiency in the striatum. Mice lacking Slc10a4 displayed impaired monoamine homeostasis and were hypersensitive to the drugs amphetamine and tranylcypromine. These findings demonstrate that SLC10A4 is capable of modulating the modulatory systems of the brain with potential clinical relevance for neurological and mental disorders.

The transcription factor encoded by Dmrt3 was found to be expressed in a population of inhibitory commissural interneurons originating from the dorsal interneuron 6 (dI6) domain in the spinal cord. In parallel, a genome-wide association study revealed that a non-sense mutation in horse DMRT3 is permissive for the ability to perform pace among other alternate gaits. Further analysis of Dmrt3 null mutant mice showed that Dmrt3 has a central role for spinal neuronal network development with consequences for locomotor behavior. The dI6 class has been suggested to take part in motor circuits but remains one of the least studied classes due to lack of molecular markers. To further investigate the Dmrt3-derived neurons, and the dI6 population in general, a Dmrt3Cre mouse line was generated which allowed for characterization on the molecular, cellular and  behavioral level. It was found that Dmrt3 neurons synapse onto motor neurons, receive extensive synaptic inputs from various neuronal sources and are rhythmically active during fictive locomotion. Furthermore, silencing of Dmrt3 neurons in Dmrt3Cre;Viaatlx/lx mice led to impaired motor coordination and alterations in gait, together demonstrating the importance of this neuronal population in the control of movement.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1026
Keyword
Synaptic vesicle transporter, Neuromodulation, Dopamine, Central Pattern Generator, Locomotion, Gait, Horse, Mouse, Commissural Inhibitory Interneuron
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-230425 (URN)978-91-554-9030-0 (ISBN)
Public defence
2014-10-24, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-10-02 Created: 2014-08-25 Last updated: 2015-01-23

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