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1.
Nutrients ; 15(5)2023 Feb 21.
Article in English | MEDLINE | ID: mdl-36904077

ABSTRACT

Nutrition during the early postnatal period can program the growth trajectory and adult size. Nutritionally regulated hormones are strongly suspected to be involved in this physiological regulation. Linear growth during the postnatal period is regulated by the neuroendocrine somatotropic axis, whose development is first controlled by GHRH neurons of the hypothalamus. Leptin that is secreted by adipocytes in proportion to fat mass is one of the most widely studied nutritional factors, with a programming effect in the hypothalamus. However, it remains unclear whether leptin stimulates the development of GHRH neurons directly. Using a Ghrh-eGFP mouse model, we show here that leptin can directly stimulate the axonal growth of GHRH neurons in vitro in arcuate explant cultures. Moreover, GHRH neurons in arcuate explants harvested from underfed pups were insensitive to the induction of axonal growth by leptin, whereas AgRP neurons in these explants were responsive to leptin treatment. This insensitivity was associated with altered activating capacities of the three JAK2, AKT and ERK signaling pathways. These results suggest that leptin may be a direct effector of linear growth programming by nutrition, and that the GHRH neuronal subpopulation may display a specific response to leptin in cases of underfeeding.


Subject(s)
Arcuate Nucleus of Hypothalamus , Axons , Leptin , Neurons , Animals , Mice , Arcuate Nucleus of Hypothalamus/metabolism , Axons/metabolism , Hypothalamus/metabolism , Leptin/metabolism , Neurons/metabolism , Animals, Suckling
2.
eNeuro ; 8(4)2021.
Article in English | MEDLINE | ID: mdl-34272258

ABSTRACT

Mutations in the X-linked cell adhesion protein PCDH19 lead to seizures, cognitive impairment, and other behavioral comorbidities when present in a mosaic pattern. Neither the molecular mechanisms underpinning this disorder nor the function of PCDH19 itself are well understood. By combining RNA in situ hybridization with immunohistochemistry and analyzing single-cell RNA sequencing datasets, we reveal Pcdh19 expression in cortical interneurons and provide a first account of the subtypes of neurons expressing Pcdh19/PCDH19, both in the mouse and the human cortex. Our quantitative analysis of the Pcdh19 mutant mouse exposes subtle changes in cortical layer composition, with no major alterations of the main axonal tracts. In addition, Pcdh19 mutant animals, particularly females, display preweaning behavioral changes, including reduced anxiety and increased exploratory behavior. Importantly, our experiments also reveal an effect of the social environment on the behavior of wild-type littermates of Pcdh19 mutant mice, which show alterations when compared with wild-type animals not housed with mutants.


Subject(s)
Cadherins , Exploratory Behavior , Animals , Cadherins/genetics , Female , Mice , Mutation/genetics , Neurons , Seizures , Social Environment
3.
Brain Neurosci Adv ; 5: 23982128211003484, 2021.
Article in English | MEDLINE | ID: mdl-33889757

ABSTRACT

Maternal obesity is associated with the development of a variety of neuropsychiatric disorders; however, the mechanisms behind this association are not fully understood. Comparison between maternal immune activation and maternal obesity reveals similarities in associated impairments and maternal cytokine profile. Here, we present a summary of recent evidence describing how inflammatory processes contribute towards the development of neuropsychiatric disorders in the offspring of obese mothers. This includes discussion on how maternal cytokine levels, fatty acids and placental inflammation may interact with foetal neurodevelopment through changes to microglial behaviour and epigenetic modification. We also propose an exosome-mediated mechanism for the disruption of brain development under maternal obesity and discuss potential intervention strategies.

4.
Curr Biol ; 28(11): 1768-1782.e4, 2018 06 04.
Article in English | MEDLINE | ID: mdl-29779877

ABSTRACT

The corpus callosum is the largest commissure in the brain, whose main function is to ensure communication between homotopic regions of the cerebral cortex. During fetal development, corpus callosum axons (CCAs) grow toward and across the brain midline and then away on the contralateral hemisphere to their targets. A particular feature of this circuit, which raises a key developmental question, is that the outgoing trajectory of post-crossing CCAs is mirror-symmetric with the incoming trajectory of pre-crossing axons. Here, we show that post-crossing CCAs switch off their response to axon guidance cues, among which the secreted Semaphorin-3C (Sema3C), that act as attractants for pre-crossing axons on their way to the midline. This change is concomitant with an upregulation of the surface protein Ephrin-B1, which acts in CCAs to inhibit Sema3C signaling via interaction with the Neuropilin-1 (Nrp1) receptor. This silencing activity is independent of Eph receptors and involves a N-glycosylation site (N-139) in the extracellular domain of Ephrin-B1. Together, our results reveal a molecular mechanism, involving interaction between the two unrelated guidance receptors Ephrin-B1 and Nrp1, that is used to control the navigation of post-crossing axons in the corpus callosum.


Subject(s)
Axons/physiology , Corpus Callosum/physiology , Ephrin-B1/genetics , Gene Expression Regulation, Developmental , Neuropilin-1/genetics , Semaphorins/genetics , Animals , Ephrin-B1/metabolism , Gene Silencing , Mice , Neuropilin-1/metabolism , Semaphorins/metabolism
5.
PLoS One ; 13(2): e0193196, 2018.
Article in English | MEDLINE | ID: mdl-29466413

ABSTRACT

Nutrition plays a critical role in programming and shaping linear growth during early postnatal life through direct action on the development of the neuroendocrine somatotropic (GH/IGF-1) axis. IGF-1 is a key factor in modulating the programming of linear growth during this period. Notably, IGF-1 preferentially stimulates axonal growth of GHRH neurons in the arcuate nucleus of the hypothalamus (Arc), which is crucial for the proliferation of somatotroph progenitors in the pituitary, thus influencing later GH secretory capacity. However, other nutrition-related hormones may also be involved. Among them, insulin shares several structural and functional similarities with IGF-1, as well as downstream signaling effectors. We investigated the role of insulin in the control of Arc axonal growth using an in vitro model of arcuate explants culture and a cell-type specific approach (GHRH-eGFP mice) under both physiological conditions (normally fed pups) and those of dietary restriction (underfed pups). Our data suggest that insulin failed to directly control axonal growth of Arc neurons or influence specific IGF-1-mediated effects on GHRH neurons. Insulin may act on neuronal welfare, which appears to be dependent on neuronal sub-populations and is influenced by the nutritional status of pups in which Arc neurons develop.


Subject(s)
Arcuate Nucleus of Hypothalamus/metabolism , Axons/metabolism , Insulin/pharmacology , Nutritional Status , Animals , Animals, Newborn , Arcuate Nucleus of Hypothalamus/cytology , Cell Culture Techniques , Cells, Cultured , Growth Hormone/metabolism , Growth Hormone-Releasing Hormone/metabolism , Insulin/metabolism , Insulin-Like Growth Factor I/metabolism , Mice , Mice, Transgenic
6.
Nat Commun ; 8: 14508, 2017 02 22.
Article in English | MEDLINE | ID: mdl-28224988

ABSTRACT

Local endocytic events involving receptors for axon guidance cues play a central role in controlling growth cone behaviour. Yet, little is known about the fate of internalized receptors, and whether the sorting events directing them to distinct endosomal pathways control guidance decisions. Here, we show that the receptor Plexin-D1 contains a sorting motif that interacts with the adaptor protein GIPC1 to facilitate transport to recycling endosomes. This sorting process promotes colocalization of Plexin-D1 with vesicular pools of active R-ras, leading to its inactivation. In the absence of interaction with GIPC1, missorting of Plexin-D1 results in loss of signalling activity. Consequently, Gipc1 mutant mice show specific defects in axonal projections, as well as vascular structures, that rely on Plexin-D1 signalling for their development. Thus, intracellular sorting steps that occur after receptor internalization by endocytosis provide a critical level of control of cellular responses to guidance signals.


Subject(s)
Axons/metabolism , Blood Vessels/metabolism , Cell Adhesion Molecules, Neuronal/metabolism , Endocytosis , Membrane Glycoproteins/metabolism , Nerve Tissue Proteins/metabolism , Signal Transduction , Adaptor Proteins, Signal Transducing/metabolism , Animals , Body Patterning , Cell Adhesion Molecules, Neuronal/chemistry , Cell Membrane/metabolism , Cytoskeletal Proteins , Endosomes/metabolism , Epistasis, Genetic , Female , Glycoproteins/metabolism , Green Fluorescent Proteins/metabolism , Growth Cones/metabolism , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins , Male , Membrane Glycoproteins/chemistry , Membrane Proteins/metabolism , Mice , Nerve Tissue Proteins/chemistry , PDZ Domains , Protein Transport , Semaphorins , ras Proteins/metabolism
8.
PLoS One ; 12(1): e0170083, 2017.
Article in English | MEDLINE | ID: mdl-28076448

ABSTRACT

Nutrition during the perinatal period programs body growth. Growth hormone (GH) secretion from the pituitary regulates body growth and is controlled by Growth Hormone Releasing Hormone (GHRH) neurons located in the arcuate nucleus of the hypothalamus. We observed that dietary restriction during the early postnatal period (i.e. lactation) in mice influences postnatal growth by permanently altering the development of the somatotropic axis in the pituitary gland. This alteration may be due to a lack of GHRH signaling during this critical developmental period. Indeed, underfed pups showed decreased insulin-like growth factor I (IGF-I) plasma levels, which are associated with lower innervation of the median eminence by GHRH axons at 10 days of age relative to normally fed pups. IGF-I preferentially stimulated axon elongation of GHRH neurons in in vitro arcuate explant cultures from 7 day-old normally fed pups. This IGF-I stimulating effect was selective since other arcuate neurons visualized concomitantly by neurofilament labeling, or AgRP immunochemistry, did not significantly respond to IGF-I stimulation. Moreover, GHRH neurons in explants from age-matched underfed pups lost the capacity to respond to IGF-I stimulation. Molecular analyses indicated that nutritional restriction was associated with impaired activation of AKT. These results highlight a role for IGF-I in axon elongation that appears to be cell selective and participates in the complex cellular mechanisms that link underfeeding during the early postnatal period with programming of the growth trajectory.


Subject(s)
Axons/drug effects , Growth Hormone-Releasing Hormone/metabolism , Insulin-Like Growth Factor I/pharmacology , Neuronal Outgrowth/drug effects , Neurons/drug effects , Animals , Animals, Newborn , Axons/metabolism , Axons/physiology , Female , Growth and Development/drug effects , Insulin-Like Growth Factor I/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/metabolism , Neurons/physiology
9.
Methods Mol Biol ; 1493: 223-235, 2017.
Article in English | MEDLINE | ID: mdl-27787854

ABSTRACT

Semaphorin guidance molecules act through different receptor complexes to activate multiple signaling cascades leading to changes in axonal growth cone behavior and morphology. We describe here approaches for studying the effect of individual Semaphorins on isolated forebrain neurons from mouse embryos and dissecting downstream signaling pathways. These approaches include the production of recombinant Semaphorin ligands, the culture of dissociated primary neurons, the manipulation of gene expression by electroporation in primary neurons, and functional assays to assess axon outgrowth and growth cone collapse.


Subject(s)
Neurons/metabolism , Semaphorins/metabolism , Signal Transduction , Animals , Axons/metabolism , Cells, Cultured , Electroporation , Gene Expression , Growth Cones/metabolism , HEK293 Cells , Humans , Mice , Prosencephalon/cytology , Prosencephalon/metabolism , Transfection
10.
Nat Commun ; 6: 7246, 2015 Jun 03.
Article in English | MEDLINE | ID: mdl-26037503

ABSTRACT

Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts.


Subject(s)
Axons/metabolism , Fornix, Brain/embryology , Glycoproteins/metabolism , Membrane Proteins/metabolism , Microtubule-Associated Proteins/genetics , Neurons/metabolism , Animals , Brain/metabolism , Brain/pathology , Cytoskeletal Proteins , Diffusion Tensor Imaging , Fornix, Brain/metabolism , Fornix, Brain/pathology , HEK293 Cells , Humans , Magnetic Resonance Imaging , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Electron , Neural Pathways/embryology , Neural Pathways/metabolism , Neurites/metabolism , Neuroanatomical Tract-Tracing Techniques , Organ Size , Semaphorins , src Homology Domains
11.
Nat Commun ; 5: 4265, 2014 Jun 27.
Article in English | MEDLINE | ID: mdl-24969029

ABSTRACT

During the development of the cerebral cortex, Cajal-Retzius (CR) cells settle in the preplate and coordinate the precise growth of the neocortex. Indeed, CR cells migrate tangentially from specific proliferative regions of the telencephalon (for example, the cortical hem (CH)) to populate the entire cortical surface. This is a very finely tuned process regulated by an emerging number of factors that has been sequentially revealed in recent years. However, the putative participation of one of the major families of axon guidance molecules in this process, the Semaphorins, was not explored. Here we show that Semaphorin-3E (Sema3E) is a natural negative regulator of the migration of PlexinD1-positive CR cells originating in the CH. Our results also indicate that Sema3E/PlexinD1 signalling controls the motogenic potential of CR cells in vitro and in vivo. Indeed, absence of Sema3E/PlexinD1 signalling increased the migratory properties of CR cells. This modulation implies negative effects on CXCL12/CXCR4 signalling and increased ADF/Cofilin activity.


Subject(s)
Cell Movement , Glycoproteins/metabolism , Membrane Glycoproteins/metabolism , Membrane Proteins/metabolism , Neocortex/embryology , Nerve Tissue Proteins/metabolism , Neurons/metabolism , RNA, Messenger/genetics , Actin Depolymerizing Factors/metabolism , Animals , Cerebral Cortex/embryology , Chemokine CXCL12/metabolism , Cytoskeletal Proteins , Destrin/metabolism , Gene Expression Regulation, Developmental , Glycoproteins/genetics , Intracellular Signaling Peptides and Proteins , Membrane Glycoproteins/genetics , Membrane Proteins/genetics , Mice , Nerve Tissue Proteins/genetics , Neurons/cytology , Receptors, CXCR4/metabolism , Semaphorins , Signal Transduction
12.
Nat Neurosci ; 15(8): 1134-43, 2012 Jul 08.
Article in English | MEDLINE | ID: mdl-22772332

ABSTRACT

Developing axons must control their growth rate to follow the appropriate pathways and establish specific connections. However, the regulatory mechanisms involved remain elusive. By combining live imaging with transplantation studies in mice, we found that spontaneous calcium activity in the thalamocortical system and the growth rate of thalamocortical axons were developmentally and intrinsically regulated. Indeed, the spontaneous activity of thalamic neurons governed axon growth and extension through the cortex in vivo. This activity-dependent modulation of growth was mediated by transcriptional regulation of Robo1 through an NF-κB binding site. Disruption of either the Robo1 or Slit1 genes accelerated the progression of thalamocortical axons in vivo, and interfering with Robo1 signaling restored normal axon growth in electrically silent neurons. Thus, modifications to spontaneous calcium activity encode a switch in the axon outgrowth program that allows the establishment of specific neuronal connections through the transcriptional regulation of Slit1 and Robo1 signaling.


Subject(s)
Axons/physiology , Calcium Signaling/genetics , Cerebral Cortex/physiology , Nerve Tissue Proteins/genetics , Receptors, Immunologic/genetics , Thalamus/physiology , Animals , Axons/pathology , Calcium/metabolism , Cerebral Cortex/growth & development , Female , Gene Expression Regulation, Developmental/genetics , Mice , Nerve Tissue Proteins/physiology , Receptors, Immunologic/physiology , Thalamus/growth & development , Roundabout Proteins
13.
Curr Biol ; 21(20): 1748-55, 2011 Oct 25.
Article in English | MEDLINE | ID: mdl-22000108

ABSTRACT

How guidance cues are integrated during the formation of complex axonal tracts remains largely unknown. Thalamocortical axons (TCAs), which convey sensory and motor information to the neocortex, have a rostrocaudal topographic organization initially established within the ventral telencephalon [1-3]. Here, we show that this topography is set in a small hub, the corridor, which contains matching rostrocaudal gradients of Slit1 and Netrin 1. Using in vitro and in vivo experiments, we show that Slit1 is a rostral repellent that positions intermediate axons. For rostral axons, although Slit1 is also repulsive and Netrin 1 has no chemotactic activity, the two factors combined generate attraction. These results show that Slit1 has a dual context-dependent role in TCA pathfinding and furthermore reveal that a combination of cues produces an emergent activity that neither of them has alone. Our study thus provides a novel framework to explain how a limited set of guidance cues can generate a vast diversity of axonal responses necessary for proper wiring of the nervous system.


Subject(s)
Axons/physiology , Growth Cones/physiology , Nerve Growth Factors/metabolism , Nerve Tissue Proteins/metabolism , Thalamus/embryology , Thalamus/physiology , Tumor Suppressor Proteins/metabolism , Animals , COS Cells , Cerebral Cortex/embryology , Cerebral Cortex/metabolism , Chlorocebus aethiops , Ephrin-A5/genetics , Ephrin-A5/metabolism , Gene Expression Regulation, Developmental , Mice , Mice, Transgenic , Nerve Growth Factors/genetics , Nerve Tissue Proteins/genetics , Netrin-1 , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Semaphorin-3A/genetics , Semaphorin-3A/metabolism , Tumor Suppressor Proteins/genetics , beta-Galactosidase/genetics , beta-Galactosidase/metabolism , Roundabout Proteins
14.
Mol Cell Neurosci ; 37(2): 222-35, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17997325

ABSTRACT

We examined whether Sema3A, which is upregulated at the site of spinal cord injury, exerts a direct effect on axons. We used ASNKL peptide that prevents specifically the inhibitory effect of Sema3A on L1/Neuropilin1 (Nrp1)-expressing axons. In the naïve mouse spinal cord, L1 is located on a subset of corticospinal axons, whereas Nrp1 is barely detectable. After contusion injury, Nrp1 is found on L1-negative immune cells, whereas its expression does not increase on severed axons. L1-expressing axons sprout extensively into the lesion site but no difference in axon density could be detected in the lesion area of mice treated with ASNKL. In agreement, these mice did not recover a better motor function than controls. Similarly, culture of neurons sensitive to ASNKL on cryosections of lesioned spinal cords revealed no effect of Sema3A. Our data indicate a limited direct effect of Sema3A on axonal growth at the site of a contusion injury, and suggest that alternative mechanisms underlie positive effects of Sema3A inhibition on motor recovery.


Subject(s)
Nerve Regeneration/physiology , Neural Cell Adhesion Molecule L1/metabolism , Recovery of Function/physiology , Semaphorin-3A/metabolism , Spinal Cord Injuries/metabolism , Animals , Axons/drug effects , Axons/metabolism , Axons/ultrastructure , Cell Line , Cells, Cultured , Feedback, Physiological/drug effects , Feedback, Physiological/physiology , Female , Growth Cones/drug effects , Growth Cones/metabolism , Growth Cones/ultrastructure , Humans , Immunohistochemistry , Mice , Mice, Inbred C57BL , Nerve Regeneration/drug effects , Neural Cell Adhesion Molecule L1/agonists , Neural Pathways/drug effects , Neural Pathways/injuries , Neural Pathways/metabolism , Neuropilin-1/metabolism , Peptide Fragments/pharmacology , Recovery of Function/drug effects , Semaphorin-3A/antagonists & inhibitors , Spinal Cord/drug effects , Spinal Cord/metabolism , Spinal Cord/physiopathology , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/physiopathology , Treatment Failure
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