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1.
J Comp Neurol ; 530(16): 2868-2880, 2022 11.
Article in English | MEDLINE | ID: mdl-35811330

ABSTRACT

Inferior olivary (IO) neurons are born in the dorsal hindbrain and migrate tangentially toward the ventral midline. During their dorsoventral migration, IO neurons extend long leading processes that cross the midline, transform into axons, and project into the contralateral cerebellum. In absence of the axon guidance receptor Robo3, IO axons fail to cross the midline and project to the ipsilateral cerebellum. Remarkably, the IO cell bodies still reach the midline where they form a nucleus of abnormal cytoarchitecture. The mechanisms underlying the migration of Robo3-deficient IO neurons are unknown. Here, we used three-dimensional imaging and transgenic mice to label subsets of IO neurons and study their migratory behavior in Robo3 knockout. We show that IO migration is delayed in absence of Robo3. Strikingly, Robo3-deficient IO neurons progress toward the midline in a direction opposite to their axons. This occurs through a change of polarity and the generation of a second leading process at the rear of the cell. These results suggest that Robo3 receptor controls the establishment of neuronal polarity and the coupling of axonogenesis and cell body migration in IO neurons.


Subject(s)
Axon Guidance , Nerve Tissue Proteins , Animals , Axons/metabolism , Cell Movement/physiology , Mice , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Neurogenesis , Neurons/metabolism , Olivary Nucleus/metabolism
2.
Cell Rep ; 34(3): 108654, 2021 01 19.
Article in English | MEDLINE | ID: mdl-33472083

ABSTRACT

In humans, execution of unimanual movements requires lateralized activation of the primary motor cortex, which then transmits the motor command to the contralateral hand through the crossed corticospinal tract (CST). Mutations in NTN1 alter motor control lateralization, leading to congenital mirror movements. To address the role of midline Netrin-1 on CST development and subsequent motor control, we analyze the morphological and functional consequences of floor plate Netrin-1 depletion in conditional knockout mice. We show that depletion of floor plate Netrin-1 in the brainstem critically disrupts CST midline crossing, whereas the other commissural systems are preserved. The only associated defect is an abnormal entry of CST axons within the inferior olive. Alteration of CST midline crossing results in functional ipsilateral projections and is associated with abnormal symmetric movements. Our study reveals the role of Netrin-1 in CST development and describes a mouse model recapitulating the characteristics of human congenital mirror movements.


Subject(s)
Axons/metabolism , Movement Disorders/metabolism , Netrin-1/metabolism , Pyramidal Tracts/metabolism , Animals , Axons/pathology , Mice , Movement Disorders/pathology , Pyramidal Tracts/pathology
3.
J Neurochem ; 153(1): 10-32, 2020 04.
Article in English | MEDLINE | ID: mdl-31630412

ABSTRACT

Perception of our environment entirely depends on the close interaction between the central and peripheral nervous system. In order to communicate each other, both systems must develop in parallel and in coordination. During development, axonal projections from the CNS as well as the PNS must extend over large distances to reach their appropriate target cells. To do so, they read and follow a series of axon guidance molecules. Interestingly, while these molecules play critical roles in guiding developing axons, they have also been shown to be critical in other major neurodevelopmental processes, such as the migration of cortical progenitors. Currently, a major hurdle for brain repair after injury or neurodegeneration is the absence of axonal regeneration in the mammalian CNS. By contrasts, PNS axons can regenerate. Many hypotheses have been put forward to explain this paradox but recent studies suggest that hacking neurodevelopmental mechanisms may be the key to promote CNS regeneration. Here we provide a seminar report written by trainees attending the second Flagship school held in Alpbach, Austria in September 2018 organized by the International Society for Neurochemistry (ISN) together with the Journal of Neurochemistry (JCN). This advanced school has brought together leaders in the fields of neurodevelopment and regeneration in order to discuss major keystones and future challenges in these respective fields.


Subject(s)
Axon Guidance/physiology , Axons/physiology , Brain/ultrastructure , Animals , Axons/ultrastructure , Brain/growth & development , Brain/physiology , Humans , Nerve Regeneration , Optic Chiasm/growth & development , Peripheral Nervous System/growth & development , Peripheral Nervous System/physiology , Spinal Cord/growth & development , Spinal Cord/physiology , Spinal Cord/ultrastructure
4.
Neuron ; 101(4): 625-634.e3, 2019 02 20.
Article in English | MEDLINE | ID: mdl-30661739

ABSTRACT

In vertebrates, commissural axons extend ventrally toward the floor plate in the spinal cord and hindbrain. Netrin-1, secreted by floor plate cells, was proposed to attract commissural axons at a distance. However, recent genetic studies in mice have shown that netrin-1 is also produced by ventricular zone (VZ) progenitors and that in the hindbrain, it represents the main source of netrin-1 for commissural axons. Here, we show that genetically deleting netrin-1 either from the VZ or the floor plate does not prevent midline crossing in the spinal cord, although axon pathfinding and fasciculation are perturbed. Strikingly, the VZ and floor plate act synergistically, as the simultaneous ablation of netrin-1 from these two sources severely impedes crossing. These results suggest that floor-plate-derived netrin-1 has a distinct impact on commissural axons in the spinal cord and hindbrain.


Subject(s)
Axon Guidance , Cerebral Ventricles/embryology , Netrin-1/metabolism , Neurons/metabolism , Rhombencephalon/embryology , Spinal Cord/embryology , Animals , Cerebral Ventricles/cytology , Cerebral Ventricles/metabolism , Female , Male , Mice , Netrin-1/genetics , Neurons/cytology , Rhombencephalon/cytology , Rhombencephalon/metabolism , Spinal Cord/cytology , Spinal Cord/metabolism
5.
Development ; 145(2)2018 01 17.
Article in English | MEDLINE | ID: mdl-29343638

ABSTRACT

During the development of the central nervous system (CNS), only motor axons project into peripheral nerves. Little is known about the cellular and molecular mechanisms that control the development of a boundary at the CNS surface and prevent CNS neuron emigration from the neural tube. It has previously been shown that a subset of spinal cord commissural axons abnormally invades sensory nerves in Ntn1 hypomorphic embryos and Dcc knockouts. However, whether netrin 1 also plays a similar role in the brain is unknown. In the hindbrain, precerebellar neurons migrate tangentially under the pial surface, and their ventral migration is guided by netrin 1. Here, we show that pontine neurons and inferior olivary neurons, two types of precerebellar neurons, are not confined to the CNS in Ntn1 and Dcc mutant mice, but that they invade the trigeminal, auditory and vagus nerves. Using a Ntn1 conditional knockout, we show that netrin 1, which is released at the pial surface by ventricular zone progenitors is responsible for the CNS confinement of precerebellar neurons. We propose, that netrin 1 distribution sculpts the CNS boundary by keeping CNS neurons in netrin 1-rich domains.


Subject(s)
Central Nervous System/embryology , Central Nervous System/metabolism , Netrin-1/metabolism , Peripheral Nervous System/embryology , Peripheral Nervous System/metabolism , Animals , Cell Movement/genetics , Cell Movement/physiology , Central Nervous System/cytology , DCC Receptor/deficiency , DCC Receptor/genetics , DCC Receptor/metabolism , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Netrin-1/deficiency , Netrin-1/genetics , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Neurons/cytology , Neurons/metabolism , Peripheral Nervous System/cytology , Pregnancy
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