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Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as markers for fast motor neurons and partition cells
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)
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
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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2010 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 518, no 12, 2284-2304 p.Article in journal (Refereed) Published
Abstract [en]

Spinal cholinergic neurons are critical for motor function in both the autonomic and somatic nervous systems and are affected in spinal cord injury and in diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. Using two screening approaches and in situ hybridization, we identified 159 genes expressed in typical cholinergic patterns in the spinal cord. These include two general cholinergic neuron markers, one gene exclusively expressed in motor neurons and nine genes expressed in unknown subtypes of somatic motor neurons. Further, we present evidence that Chondrolectin (Chodl) is a novel genetic marker for putative fast motor neurons and that estrogen-related receptor b (ERRb) is a candidate genetic marker for slow motor neurons. In addition, we suggest paired-like homeodomain transcription factor 2 (Pitx2) as a marker for cholinergic partition cells.

Place, publisher, year, edition, pages
2010. Vol. 518, no 12, 2284-2304 p.
Keyword [en]
mouse genetics, neuronal network, interneuron, motor neuron, spinal cord, genetic screen
National Category
Medical and Health Sciences
Research subject
Developmental Neurosciences; Genetics
Identifiers
URN: urn:nbn:se:uu:diva-109916DOI: 10.1002/cne.22332ISI: 000277580600007PubMedID: 20437528OAI: oai:DiVA.org:uu-109916DiVA: diva2:274579
Available from: 2009-10-30 Created: 2009-10-29 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Studies of Spinal Motor Control Networks in Genetically Modified Mouse Models
Open this publication in new window or tab >>Studies of Spinal Motor Control Networks in Genetically Modified Mouse Models
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Spinal neurons are important in several aspects motor control. For example, the neurons essential for locomotor movements reside in the ventral spinal cord. In this thesis, different motor control functions are being related to neuronal populations defined by their common expression of a gene.

First, a targeted disruption of the gene for vesicular glutamate transporter 2 (Vglut2/ Slc17a6) is described. The mutant animals die at birth because of their inability to breathe. The neuronal network in the brainstem, responsible for inspiration, was shown to become non-functional by the targeted deletion of Vglut2. To our surprise, it was still possible to induce rhythmic activity with normal left/right alternation in spinal cords isolated from VGLUT2-null embryos. Inconsistent reports of Vglut1 expression in the spinal cord made us re-evaluate the Vglut1 and Vglut2 expressions. While Vglut2 expression was widespread in the spinal cord, Vglut1 expression was restricted to a few cells dorsal to the central canal.  Taken together, the data suggest that, glutamatergic signaling is mandatory to drive the bilateral breathing, but not needed for coordination of basal alternating spinal locomotor rhythm.

Next, a screen for genes with restricted ventral expression was made. Some of the genes found could be connected to the characteristics of specific neuronal cell populations. For example, fast motor neurons were shown to express the genes Calca and Chodl. Further, we found the Chrna2 expression selectively in putative Renshaw cells. It seems likely that the gene product, the alpha2 subunit of the nicotinergic receptor, could be linked to the unique connection of motor neurons to Renshaw cells. We used the Chrna2 promoter to drive expression of Cre recombinase in a transgenic mouse. The Cre activity was present in most neurons labeled with Renshaw cell markers, which should make it a useful tool for functional studies of this population. The studies presented here show how the genes expressed in subsets of neurons can be used to target populations of neurons for functional studies of neuronal systems.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 45 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 497
Keyword
acetyl choline, central nervous system, central pattern generator, Cre recombinase, development, genetic screen, glutamate, interneuron, motor neuron, mouse, mouse genetics, movement, network, neuronal network, nicotinic receptors, physiology, Renshaw cell, rhythm, spinal cord, transmitter
National Category
Neurosciences Neurosciences Physiology Physiology Physiology
Research subject
Developmental Neurosciences
Identifiers
urn:nbn:se:uu:diva-109889 (URN)978-91-554-7654-0 (ISBN)
Public defence
2009-12-11, B22, BMC, Husarg 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2009-11-20 Created: 2009-10-29 Last updated: 2009-11-20Bibliographically approved
2. 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
3. Neural Control of Movement: Motor Neuron Subtypes, Proprioception and Recurrent Inhibition
Open this publication in new window or tab >>Neural Control of Movement: Motor Neuron Subtypes, Proprioception and Recurrent Inhibition
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Movement is central for life, and all animals depend on accurate regulation of movement for purposeful behavior. There is great diversity of movements, ranging between simple and vital breathing movements to minute and subtle movements of the face used to communicate emotions. Consequently, motor neurons, which are the only route of central nervous system output, are essential for all motor behaviors. To control the many motor behaviors expressed by an animal, motor neurons are exposed to a large number and variety of modulating synaptic inputs and have evolved into subtypes with specific functions. In this thesis, motor neuron subtypes and the synaptic input to motor neurons from Renshaw cells and Ia afferents have been studied. Novel molecular markers that identify subtypes of motor neurons are described. Three markers, Chodl, Calca and ERRβ, have been used to study the degeneration of subtypes of motor neurons in a mouse model of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Another marker, 5-ht1d, has been used to record the electrophysiological character of gamma motor neurons. In mice that lack 5-ht1d, motor neurons develop with reduced proprioceptive input. Remarkably, these mice had fewer foot faults than control animals when challenged to cross a narrow beam suggesting that the amplitude of monosynaptic proprioceptive input to motor neurons is not essential for motor coordination. In a final set of experiments, genetic removal of vesicular transport of neurotransmitter from Renshaw cells suggest that Renshaw cells are not integral for motor circuit function or motor behaviors. However, they are involved in the development of motor circuits in the spinal cord. Together, this thesis provides novel molecular tools for studies of motor neuron subtypes and novel data regarding the development and function of spinal motor circuits.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 660
Keyword
motor neuron, proprioception, recurrent inhibition, molecular marker, Ia afferent, development, transgenic mice, Renshaw cell
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-147361 (URN)978-91-554-8043-1 (ISBN)
Public defence
2011-05-14, B21, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2011-04-20 Created: 2011-02-25 Last updated: 2011-05-05Bibliographically approved

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Gezelius, HenrikKullander, Klas

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