| 1. |
- Andersson, Lisa, et al.
(författare)
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Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 488:7413, s. 642-646
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Enjin, Anders, et al.
(författare)
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Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as markers for fast motor neurons and partition cells
- 2010
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Ingår i: Journal of Comparative Neurology. - : Wiley. - 0021-9967 .- 1096-9861. ; 518:12, s. 2284-2304
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Hanell, Anders, et al.
(författare)
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Functional and Histological Outcome after Focal Traumatic Brain Injury Is Not Improved in Conditional EphA4 Knockout Mice
- 2012
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 29:17, s. 2660-2671
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the role of the axon guidance molecule EphA4 following traumatic brain injury (TBI) in mice. Neutralization of EphA4 improved motor function and axonal regeneration following experimental spinal cord injury (SCI). We hypothesized that genetic absence of EphA4 could improve functional and histological outcome following TBI. Using qRT-PCR in wild-type (WT) mice, we evaluated the EphA4 mRNA levels following controlled cortical impact (CCI) TBI or sham injury and found it to be downregulated in the hippocampus (p < 0.05) but not the cortex ipsilateral to the injury at 24 h post-injury. Next, we evaluated the behavioral and histological outcome following CCI using WT mice and Emx1-Cre-driven conditional knockout (cKO) mice. In cKO mice, EphA4 was completely absent in the hippocampus and markedly reduced in the cortical regions from embryonic day 16, which was confirmed using Western blot analysis. EphA4 cKO mice had similar learning and memory abilities at 3 weeks post-TBI compared to WT controls, although brain-injured animals performed worse than sham-injured controls (p < 0.05). EphA4 cKO mice performed similarly to WT mice in the rotarod and cylinder tests of motor function up to 29 days post-injury. TBI increased cortical and hippocampal astrocytosis (GFAP immunohistochemistry, p < 0.05) and hippocampal sprouting (Timm stain, p < 0.05) and induced a marked loss of hemispheric tissue (p < 0.05). EphA4 cKO did not alter the histological outcome. Although our results may argue against a beneficial role for EphA4 in the recovery process following TBI, further studies including post-injury pharmacological neutralization of EphA4 are needed to define the role for EphA4 following TBI.
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| 4. |
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| 5. |
- Rabe Bernhardt, Nadine, 1978-, et al.
(författare)
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DCC mediated axon guidance of spinal interneurons is essential for normal locomotor central pattern generator function
- 2012
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 366:2, s. 279-289
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Rabe, Nadine, 1978-, et al.
(författare)
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Netrin-1-Dependent Spinal Interneuron Subtypes Are Required for the Formation of Left-Right Alternating Locomotor Circuitry
- 2009
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 29:50, s. 15642-15649
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Vallstedt, Anna, et al.
(författare)
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Dorsally derived spinal interneurons in locomotor circuits
- 2013
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Ingår i: Neurons, Circuitry, and Plasticity in the Spinal Cord and Brainstem. - : Wiley. - 9781573318747 ; , s. 32-42
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Konferensbidrag (refereegranskat)abstract
- During neuronal circuit formation, axons are guided to their targets by the help of axon guidance molecules, which are required for establishing functional circuits. A promising system to dissect the development and functionalities of neuronal circuitry is the spinal cord central pattern generator (CPG) for locomotion, which converts a tonic supraspinal drive to rhythmic and coordinated movements. Here we describe concepts arising from genetic studies of the locomotor network with a focus on the position and roles of commissural interneurons. In particular, this involves studies of several families of axon guidance molecules relevant for midline crossing, the Eph/ephrins and Netrin/DCC. Effects on developing commissural interneurons in mice with aberrant midline axon guidance capabilities suggest that, in addition to ventral populations, dorsal commissural interneurons also play a role in coordinating locomotor circuitry. Recent findings implicate the novel dI6 interneuron marker Dmrt3 in this role. Strikingly, mutations in Dmrt3 result in divergent gait patterns in both mice and horses.
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| 8. |
- Vallstedt, Anna
(författare)
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The role of Nkx proteins neuronal and glial specification
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During development, different classes of neurons and glia are generated from proliferative progenitor cells lining the ventricles of the brain and the lumen of the spinal cord. A central issue in developmental neuroscience is to understand the mechanisms by which these cells are generated in space and over time. In the ventral spinal cord, the expression profile of homeodomain (HD) proteins defines five progenitor domains that each will give rise to a distinct type of neuron. Two closely related HD transcriptional repressors, Nkx6.1 and Nkx6.2 (Nkx6), are expressed by progenitors of the ventral spinal cord. We provide evidence that different levels of Nkx6 repressor activity in progenitor cells are a critical determinant of ventral neuronal fate, assigning both redundant and specific roles for these proteins in neuronal specification. A reduction in Nkx6 activity further permits V0 interneurons to be generated from progenitors that lack HD proteins normally required for their generation, providing direct evidence for a model where HD proteins direct specific cell fates by actively repressing the expression of transcription factors that direct alternative fates. In the ventral spinal cord, sMNs and oligodendrocyte precursors (OLPs) are sequentially generated from a domain defined by the expression of Olig2. We show that the generation of sMNs and OLPs in the ventral spinal cord is essentially missing in mice lacking Nkx6 function. In contrast, the same HD proteins instead act to suppress OLP specification in the ventral hindbrain. The divergent roles for Nkx6 proteins seem to reflect that OLPs in the spinal cord and hindbrain are produced by distinct ventral progenitor domains. While a ventral specification of OLPs is well established, it has remained unclear whether also more dorsal progenitor cells give rise to oligodendrocytes. We provide in vivo and in vitro evidence that oligodendrocytes are produced also by dorsal progenitors in the spinal cord and hindbrain and that the specification of these cells may result from the progressive evasion of dorsal BUT signalling over time. Together, our data suggest that oligodendrocytes are generated from multiple dorsoventral origins in the spinal cord and hindbrain, and indicate that the activation of Olig2 at different positions is controlled by distinct genetic programs. The observation that the loss of sMNs in the spinal cord of Nkx6 mutant mice correlates with an extinguished expression of the sMN determinant Olig2 has led to a model where Nkx6 proteins act strictly upstream of Olig2. However, in the hindbrain of Nkx6 mutant mice the initial expression of Olig2 is intact and despite this all sMNs are missing, indicating a parallel requirement for Nkx6 and Olig2 proteins in the generation of sMNs. Visceral motor neurons (vMNs) are generated immediately ventral to sMNs. The transcription factor Phox2b has been found to be an important determinant of these cells, but other factors involved have not been identified. We show that the HD protein Nkx2.2 is sufficient to mediate the expression of Phox2b. Furthermore, while the activities of Nkx6.1 and Nkx6.2 are dispensable for the initial generation of vMNs, they are required to prevent a parallel program of more dorsal interneuronal differentiation and to ensure a proper migration and axonal projection formation of vMNs. Thus, Nkx2 and Nkx6 proteins appear to have complementary roles in the establishment of vMN identity in the hindbrain. Taken together, our data suggest that both visceral and somatic motor neuron differentiation rely on the combined activity of cell intrinsic determinants, rather than on a singe key determinant of neuronal cell fate. Neuronal diversity is established by mechanisms that operate in space and over time. Advances have been made in regard to the mechanisms that restrict and direct neuronal generation in space, but less is known about the mechanisms that underlie how neural progenitors produce distinct types of neurons in a specific temporal order. We addressed this issue by studying a population of progenitor cells in the ventral hindbrain that gives rise to vMNs and serotonergic (S) neurons. Each hindbrain segment, or rhombomere (r), initially generates vMNs, but all the rhombomeres except for r4 switch to producing S neurons at a defined time point. We found that the temporal and spatial generation of vMNs and S neurons critically relies on the integrated activity of Nkx- and Hox-class HD proteins. A primary function of these proteins is to coordinate the activation of Phox2b in space and time. Phox2b, in turn, functions as a binary switch in deciding whether progenitors differentiate into vMNs or serotonergic neurons. Taken together, these data indicate that determinants that control spatial patterning may be associated also with temporal patterning and require that expression patterns are dynamic and modulated over time.
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