CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment.

The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.

Humid heat environment causes anxiety-like disorder via impairing gut microbiota and bile acid metabolism in mice.

Climate and environmental changes threaten human mental health, but the impacts of specific environmental conditions on neuropsychiatric disorders remain largely unclear. Here, we show the impact of a humid heat environment on the brain and the gut microbiota using a conditioned housing male mouse model. We demonstrate that a humid heat environment can cause anxiety-like behaviour in male mice. Microbial 16 S rRNA sequencing analysis reveals that a humid heat environment caused gut microbiota dysbiosis (e.g., decreased abundance of Lactobacillus murinus), and metabolomics reveals an increase in serum levels of secondary bile acids (e.g., lithocholic acid). Moreover, increased neuroinflammation is indicated by the elevated expression of proinflammatory cytokines in the serum and cortex, activated PI3K/AKT/NF-κB signalling and a microglial response in the cortex. Strikingly, transplantation of the microbiota from mice reared in a humid heat environment readily recapitulates these abnormalities in germ-free mice, and these abnormalities are markedly reversed by Lactobacillus murinus administration. Human samples collected during the humid heat season also show a decrease in Lactobacillus murinus abundance and an increase in the serum lithocholic acid concentration. In conclusion, gut microbiota dysbiosis induced by a humid heat environment drives the progression of anxiety disorders by impairing bile acid metabolism and enhancing neuroinflammation, and probiotic administration is a potential therapeutic strategy for these disorders.

Celsr2-mediated morphological polarization and functional phenotype of reactive astrocytes in neural repair.

Neural repair is highly influenced by reactive astrocytes. Atypical cadherin Celsr2 regulates neuron development and axon regeneration, while its role in glial cells remains unexplored. In this study, we show that Celsr2 is highly expressed in spinal astrocytes of adult mice, and knockout of Celsr2 results in reactive astrocytes with longer protrusions preferentially orientated towards lesion borders in culture scratch assay and injured spinal cord, and elevation of total and active Cdc42 and Rac1 protein in western blots. Inactivation of Celsr2 enhances calcium influx in reactive astrocytes in time-lapse imaging. Morphological phenotypes of cultured Celsr2-/- astrocytes are rescued by Cdc42 or Rac1 inhibitors. Following spinal cord injury (SCI), Celsr2-/- mice exhibit smaller lesion cavity and glial scar, enhanced fiber regeneration, weaker microglial response, and improved functional recovery than control animals. Similar phenotypes are found in mice with conditional knockout of Celsr2 in astrocytes. In Celsr2-/- mice, astrocyte phenotype is changed and neuroinflammation is alleviated after injury. Inhibiting Cdc42/Rac1 activities compromises astrocyte polarization and the improvement of neural repair and functional recovery in Celsr2-/- mice with SCI. In conclusion, Celsr2 regulates morphological polarization and functional phenotype of reactive astrocytes and inactivating Celsr2 is a potential therapeutic strategy for neural repair.

Celsr2 Knockout Alleviates Inhibitory Synaptic Stripping and Benefits Motoneuron Survival and Axon Regeneration After Branchial Plexus Avulsion.

Axotomy-induced synaptic stripping modulates survival and axon regeneration of injured motoneurons. Celsr2 is supposed to mediate homophilic interactions of neighboring cells during development, and its role in synaptic stripping remains unknow. In a model of brachial plexus avulsion, Celsr2 knockout improved functional recovery, motoneuron survival, and axon regeneration. Celsr2 was indicated to express in spinal motoneurons, excitatory and inhibitory interneurons, astrocytes, and a subset of oligodendrocytes using Celsr2LacZ mice. Double immunostaining showed that the coverage of inhibitory and excitatory vesicles on injured motoneurons were remarkably reduced after injury, whereas more inhibitory vesicles were maintained in Celsr2-/- mutants than control mice. In the ultrastructure, the density of inhibitory F-boutons on injured motoneurons was higher in Celsr2-/- mutants than controls. Conditional knockout of Celsr2 in astrocytes or oligodendrocytes showed the similar axotomy-induced synaptic withdrawal to the control. RNAseq of injured spinal samples identified 12 MHC I molecules with significant changes between Celsr2-/- and control mice. After injury, expression of MHC I surrounding injured motoneurons was increased, particularly high in Celsr2-/- mutants. In conclusion, Celsr2 knockout enhances MHC I signaling, alleviates inhibitory synaptic stripping cell-autonomously, and contributes to motoneuron survival and regeneration, and Celsr2 is a potential target for neural repair.

Planar cell polarity protein Celsr2 maintains structural and functional integrity of adult cortical synapses.

A few developmental genes remain persistently expressed in the adult stage, whilst their potential functions in the mature brain remain underappreciated. Here, we report the unexpected importance of Celsr2, a core Planar cell polarity (PCP) component, in maintaining the structural and functional integrity of adult neocortex. Celsr2 is highly expressed during development and remains expressed in adult neocortex. In vivo synaptic imaging in Celsr2 deficient mice revealed alterations in spinogenesis and reduced neuronal calcium activities, which are associated with impaired motor learning. These phenotypes were accompanied with anomalies of both postsynaptic organization and presynaptic vesicles. Knockout of Celsr2 in adult mice recapitulated those features, further supporting the role of Celsr2 in maintaining the integrity of mature cortex. In sum, our data identify previously unrecognized roles of Celsr2 in the maintenance of synaptic function and motor learning in adulthood.

Celsr2 regulates NMDA receptors and dendritic homeostasis in dorsal CA1 to enable social memory.

Social recognition and memory are critical for survival. The hippocampus serves as a central neural substrate underlying the dynamic coding and transmission of social information. Yet the molecular mechanisms regulating social memory integrity in hippocampus remain unelucidated. Here we report unexpected roles of Celsr2, an atypical cadherin, in regulating hippocampal synaptic plasticity and social memory in mice. Celsr2-deficient mice exhibited defective social memory, with rather intact levels of sociability. In vivo fiber photometry recordings disclosed decreased neural activity of dorsal CA1 pyramidal neuron in Celsr2 mutants performing social memory task. Celsr2 deficiency led to selective impairment in NMDAR but not AMPAR-mediated synaptic transmission, and to neuronal hypoactivity in dorsal CA1. Those activity changes were accompanied with exuberant apical dendrites and immaturity of spines of CA1 pyramidal neurons. Strikingly, knockdown of Celsr2 in adult hippocampus recapitulated the behavioral and cellular changes observed in knockout mice. Restoring NMDAR transmission or CA1 neuronal activities rescued social memory deficits. Collectively, these results show a critical role of Celsr2 in orchestrating dorsal hippocampal NMDAR function, dendritic and spine homeostasis, and social memory in adulthood.

Celsr3 Inactivation in the Brainstem Impairs Rubrospinal Tract Development and Mouse Behaviors in Motor Coordination and Mechanic-Induced Response.

Inactivation of Celsr3 in the forebrain results in defects of longitudinal axonal tracts such as the corticospinal tract. In this study, we inactivated Celsr3 in the brainstem using En1-Cre mice (Celsr3 cKO) and analyzed axonal and behavioral phenotypes. Celsr3 cKO animals showed an 83% reduction of rubrospinal axons and 30% decrease of corticospinal axons in spinal segments, associated with increased branching of dopaminergic fibers in the ventral horn. Decreases of spinal motoneurons, neuromuscular junctions, and electromyographic signal amplitude of the biceps were also found in mutant animals. Mutant mice had impaired motor coordination and defective response to heavy mechanical stimulation, but no disability in walking and food pellet handling. Transsynaptic tracing demonstrated that rubrospinal axons synapse on spinal neurons in the deep layer of the dorsal horn, and mechanical stimulation of hindpaws induced strong calcium signal of red nuclei in control mice, which was less prominent in mutant mice. In conclusion, Celsr3 regulates development of spinal descending axons and the motor network in cell and non-cell autonomous manners, and the maturation of the rubrospinal system is required for motor coordination and response to mechanical stimulation.

In-utero exposure to air pollution and early-life neural development and cognition.

Air pollution remains one of the major health threats around the world. Compared to adults, foetuses and infants are more vulnerable to the effects of environmental toxins. Maternal exposure to air pollution causes several adverse birth outcomes and may lead to life-long health consequences. Given that a healthy intrauterine environment is a critical factor for supporting normal foetal brain development, there is a need to understand how prenatal exposure to air pollution affects brain health and results in neurological dysfunction. This review summarised the current knowledge on the adverse effects of prenatal air pollution exposure on early life neurodevelopment and subsequent impairment of cognition and behaviour in childhood, as well as the potential of early-onset neurodegeneration. While inflammation, oxidative stress, and endoplasmic reticulum are closely involved in the physiological response, sex differences also occur. In general, males are more susceptible than females to the adverse effect of in-utero air pollution exposure. Considering the evidence provided in this review and the rising concerns of global air pollution, any efforts to reduce pollutant emission or exposure will be protective for the next generation.

Inactivating Celsr2 promotes motor axon fasciculation and regeneration in mouse and human.

Understanding new modulators of axon regeneration is central to neural repair. Our previous work demonstrated critical roles of atypical cadherin Celsr2 during neural development, including cilia organization, neuron migration and axon navigation. Here, we address its role in axon regeneration. We show that Celsr2 is highly expressed in both mouse and human spinal motor neurons. Celsr2 knockout promotes axon regeneration and fasciculation in mouse cultured spinal explants. Similarly, cultured Celsr2 mutant motor neurons extend longer neurites and larger growth cones, with increased expression of end-binding protein 3 and higher potassium-induced calcium influx. Mice with Celsr2 conditional knockout in spinal motor neurons do not exhibit any behavioural deficits; however, after branchial plexus injury, axon regeneration and functional forelimb locomotor recovery are significantly improved. Similarly, knockdown of CELSR2 using shRNA interference in cultured human spinal motor explants and motor neurons increases axonal fasciculation and growth. In mouse adult spinal cord after root avulsion, in mouse embryonic spinal cords, and in cultured human motor neurons, Celsr2 downregulation is accompanied by increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun. In conclusion, Celsr2 negatively regulates motor axon regeneration and is a potential target to improve neural repair.

Sex bias in alcohol research: A 20-year comparative study.

We aimed to assess the sex-inclusive and sex-based analysis bias in alcohol research for the past 20 years. Data were abstracted from 2988 original research articles published from 2000 through 2019 in 51 representative journals across 9 biomedical disciplines. An analysis in 5-year intervals revealed that the percentage of studies using participants of both sexes was significantly higher between 2015 and 2019 than between 2000 and 2014. When stratified, clinical studies showed a higher percentage of both-sex studies compared to basic studies using animals. The reasons for the use of single-sex cohorts mainly included insufficient participant numbers and misconceptions surrounding the hormonal variability of females. Implementation of the NIH SABV policy promoted the ratio of NIH-funded papers with sex-based analyses. In conclusion, sex bias in alcohol-related biomedical studies has improved over the past 20 years, particularly after the implementation of the SABV policy. Although clinical studies increasingly included sex-based analysis, basic studies were biased towards the use of males.

Celsr3 is required for Purkinje cell maturation and regulates cerebellar postsynaptic plasticity.

Atypical cadherin Celsr3 is critical for brain embryonic development, and its role in the postnatal cerebellum remains unknown. Using Celsr3-GFP mice, Celsr3 shows high expression in postnatal Purkinje cells (PCs). Mice with conditional knockout (cKO) of Celsr3 in postnatal PCs exhibit deficit in motor coordination and learning, atrophic PC dendrites, and decreased synapses. Whole-PC recording in cerebellar slices discloses a reduction frequency of mEPSC and defective postsynaptic plasticity (LTP and LTD) in Celsr3 cKO mutants. Wnt5a perfusion enhances LTP formation, which could be occluded by cAMP agonist and diminished by cAMP antagonist in control, but not in Celsr3 cKO or Fzd3 cKO cerebellar slices. Celsr3 cKO resulted in the failure of mGluR1 agonist-induced LTD and paired stimulation-induced PKCα overexpression in PC dendrites, and downregulation of mGluR1 expression compvared to controls. In conclusion, Celsr3 is required for PCs maturation and regulates postsynaptic LTP and LTD through Wnt5a/cAMP and mGluR1/PKCα signaling respectively.

Human adipose tissue- and umbilical cord-derived stem cells: which is a better alternative to treat spinal cord injury?

Multiple types of stem cells have been proposed for the treatment of spinal cord injury, but their comparative information remains elusive. In this study, a rat model of T10 contusion spinal cord injury was established by the impactor method. Human umbilical cord-derived mesenchymal stem cells (UCMSCs) or human adipose tissue-derived mesenchymal stem cells (ADMSCs) (2.5 µL/injection site, 1 × 105 cells/µL) was injected on rostral and caudal of the injury segment on the ninth day after injury. Rats injected with mesenchymal stem cell culture medium were used as controls. Our results show that although transplanted UCMSCs and ADMSCs failed to differentiate into neurons or glial cells in vivo, both significantly improved motor and sensory function. After spinal cord injury, UCMSCs and ADMSCs similarly promoted spinal neuron survival and axonal regeneration, decreased glial scar and lesion cavity formation, and reduced numbers of active macrophages. Bio-Plex analysis of spinal samples showed a specific increase of interleukin-10 and decrease of tumor necrosis factor α in the ADMSC group, as well as a downregulation of macrophage inflammatory protein 3α in both UCMSC and ADMSC groups at 3 days after cell transplantation. Upregulation of interleukin-10 and interleukin-13 was observed in both UCMSC and ADMSC groups at 7 days after cell transplantation. Isobaric tagging for relative and absolute quantitation proteomics analyses showed that UCMSCs and ADMSCs induced changes of multiple genes related to axonal regeneration, neurotrophy, and cell apoptosis in common and specific manners. In conclusion, UCMSC and ADMSC transplants yielded quite similar contributions to motor and sensory recovery after spinal cord injury via anti-inflammation and improved axonal growth. However, there were some differences in cytokine and gene expression induced by these two types of transplanted cells. Animal experiments were approved by the Laboratory Animal Ethics Committee at Jinan University (approval No. 20180228026) on February 28, 2018, and the application of human stem cells was approved by the Medical Ethics Committee of Medical College of Jinan University of China (approval No. 2016041303) on April 13, 2016.

Early Forebrain Neurons and Scaffold Fibers in Human Embryos.

Neural progenitor proliferation, neuronal migration, areal organization, and pioneer axon wiring are critical events during early forebrain development, yet remain incompletely understood, especially in human. Here, we studied forebrain development in human embryos aged 5 to 8 postconceptional weeks (WPC5-8), stages that correspond to the neuroepithelium/early marginal zone (WPC5), telencephalic preplate (WPC6 & 7), and incipient cortical plate (WPC8). We show that early telencephalic neurons are formed at the neuroepithelial stage; the most precocious ones originate from local telencephalic neuroepithelium and possibly from the olfactory placode. At the preplate stage, forebrain organization is quite similar in human and mouse in terms of areal organization and of differentiation of Cajal-Retzius cells, pioneer neurons, and axons. Like in mice, axons from pioneer neurons in prethalamus, ventral telencephalon, and cortical preplate cross the diencephalon-telencephalon junction and the pallial-subpallial boundary, forming scaffolds that could guide thalamic and cortical axons at later stages. In accord with this model, at the early cortical plate stage, corticofugal axons run in ventral telencephalon in close contact with scaffold neurons, which express CELSR3 and FZD3, two molecules that regulates formation of similar scaffolds in mice.

Triangeliphthalides A-D: bioactive phthalide trimers with new skeletons from Angelica sinensis and their production mechanism.

Triangeliphthalides A-D (1-4), four novel phthalide trimers with two new linkage styles, were isolated from Angelica sinensis, together with two related phthalide dimers (5-6). Their structures including absolute configurations were determined. The production mechanism of phthalide polymers was proposed, and their bioactivities were also evaluated.

Wheel Running Improves Motor Function and Spinal Cord Plasticity in Mice With Genetic Absence of the Corticospinal Tract.

Our previous studies showed that mutant mice with congenital absence of the corticospinal tract (CST) undergo spontaneous remodeling of motor networks to partially compensate for absent CST function. Here, we asked whether voluntary wheel running could further improve locomotor plasticity in CST-deficient mice. Adult mutant mice were randomly allocated to a "runners" group with free access to a wheel, or a "non-runners" group with no access to a wheel. In comparison with non-runners, there was a significant motor improvement including fine movement, grip strength, decreased footslip errors in runners after 8-week training, which was supported by the elevated amplitude of electromyography recording and increased neuromuscular junctions in the biceps. In runners, terminal ramifications of monoaminergic and rubrospinal descending axons were significantly increased in spinal segments after 12 weeks of exercise compared to non-runners. 5-ethynyl-2'-deoxyuridine (EDU) labeling showed that proliferating cells, 90% of which were Olig2-positive oligodendrocyte progenitors, were 4.8-fold more abundant in runners than in non-runners. In 8-week runners, RNAseq analysis of spinal samples identified 404 genes up-regulated and 398 genes down-regulated, and 69 differently expressed genes involved in signal transduction, among which the NF-κB, PI3K-Akt and cyclic AMP (cAMP) signaling were three top pathways. Twelve-week training induced a significant elevation of postsynaptic density protein 95 (PSD95), synaptophysin 38 and myelin basic protein (MBP), but not of brain derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and insulin like growth factor-1 (IGF-1). Thus, locomotor training activates multiple signaling pathways, contributes to neural plasticity and functional improvement, and might palliate locomotor deficits in patients.

The role of Celsr3 in the development of central somatosensory projections from dorsal root ganglia.

Dorsal root ganglion (DRG) neurons receive peripheral somatosensory information and send orderly projections to second-order relay nuclei in the spinal cord and in the brainstem. Atypical cadherin Celsr3 is known to play a critical role in wiring of several central and peripheral axons. Although Celsr3 mRNA is heavily expressed in DRG neurons, its role in the development of somatosensory projections remains unexplored. Here we assessed the role of Celsr3 in DRG using conditional gene inactivation in crosses with Wnt1-Cre mice. Using Celsr3-GFP transgenic mice, we found that Celsr3 was highly expressed in different DRG cells, such as Pavalbumin-, TrkB-, and calcitonin gene-related peptide (CGRP)-positive neurons. Wnt1-Cre;Celsr3f/- animals survived for a few weeks and looked smaller than littermate controls. DiI tracing showed that early DRG axons entered the spinal cord and reached spinal cord targets similarly in mutant and control mice. CGRP-positive fiber density was significantly decreased in lamina I in the mutant versus control spinal cord at postnatal day (P) 7 and P14. Furthermore, more Pavalbumin-positive fibers invaded the gray matter and made more contacts with spinal motor neurons in mutant than in control samples. Behavioral analysis showed that mutant animals were less sensitive to pain and more sensitive to mechanical stimulation than controls. In conclusion, Celsr3 is dispensable for the patterning of central DRG projections, but it regulates for the fine mapping of sensory fibers in the gray matter, which is important for somatosensory processing.

The atypical cadherin Celsr1 functions non-cell autonomously to block rostral migration of facial branchiomotor neurons in mice.

The caudal migration of facial branchiomotor (FBM) neurons from rhombomere (r) 4 to r6 in the hindbrain is an excellent model to study neuronal migration mechanisms. Although several Wnt/Planar Cell Polarity (PCP) components are required for FBM neuron migration, only Celsr1, an atypical cadherin, regulates the direction of migration in mice. In Celsr1 mutants, a subset of FBM neurons migrates rostrally instead of caudally. Interestingly, Celsr1 is not expressed in the migrating FBM neurons, but rather in the adjacent floor plate and adjoining ventricular zone. To evaluate the contribution of different expression domains to neuronal migration, we conditionally inactivated Celsr1 in specific cell types. Intriguingly, inactivation of Celsr1 in the ventricular zone of r3-r5, but not in the floor plate, leads to rostral migration of FBM neurons, greatly resembling the migration defect of Celsr1 mutants. Dye fill experiments indicate that the rostrally-migrated FBM neurons in Celsr1 mutants originate from the anterior margin of r4. These data suggest strongly that Celsr1 ensures that FBM neurons migrate caudally by suppressing molecular cues in the rostral hindbrain that can attract FBM neurons.

Celsr3 and Fzd3 Organize a Pioneer Neuron Scaffold to Steer Growing Thalamocortical Axons.

Celsr3 and Fzd3 regulate the development of reciprocal thalamocortical projections independently of their expression in cortical or thalamic neurons. To understand this cell non autonomous mechanism further, we tested whether Celsr3 and Fzd3 could act via Isl1-positive guidepost cells. Isl1-positive cells appear in the forebrain at embryonic day (E) 9.5-E10.5 and, from E12.5, they form 2 contingents in ventral telencephalon and prethalamus. In control mice, corticothalamic axons run in the ventral telencephalic corridor in close contact with Isl1-positive cells. When Celsr3 or Fzd3 is inactivated in Isl1-expressing cells, corticofugal fibers stall and loop in the ventral telencephalic corridor of high Isl1 expression, and thalamic axons fail to cross the diencephalon-telencephalon junction (DTJ). At E12.5, before thalamic and cortical axons emerge, pioneer projections from Isl1-positive cells cross the DTJ from both sides in control but not mutant embryos. These early projections appear to act like a bridge to guide later growing thalamic axons through the DTJ. Our data suggest that Celsr3 and Fzd3 orchestrate the formation of a scaffold of pioneer neurons and their axons. This scaffold extends from prethalamus to ventral telencephalon and subcortex, and steers reciprocal corticothalamic fibers.

Frizzled3 Shapes the Development of Retinal Rod Bipolar Cells.

PURPOSE: Frizzled3 (Fzd3), a member of the core planar cell polarity (PCP) family in mammals, contributes to visual development by guiding axonal projections of some retinal ganglion cells. However, its other functions in the maturation of the visual system, especially the retina, remain elusive. The present study explores the role of Fzd3 in retinal development by focusing on rod bipolar cells (RBCs). METHODS: Frizzled3 was conditionally removed from the retina of Isl1-Cre;Fzd3f/- mice using the Cre-loxP system. Electroretinograms (ERGs) were performed to measure the light response of retinas. Frizzled3 expression was monitored by ß-galactosidase (ß-gal) staining and anti-ß-gal immunostaining. Immunofluorescence was used to examine cellular distribution and morphology during development, and electron microscopy was applied to visualize the dendritic invaginations of RBCs. RESULTS: Electroretinograms showed decreased b-wave amplitudes, and lower b- to a-wave ratios in Isl1-Cre;Fzd3f/- than in control (Isl1-Cre;Fzd3f/+) mice. In RBCs, where Fzd3 was expressed and inactivated, the planar organization, shape, and orientation of somas were disrupted. From P10, dendrites of these RBCs displayed reduced arborization with mistargeting. Furthermore, their dendritic invaginations into rod terminals were suppressed, and the density of rod ribbons in the OPL was reduced. CONCLUSIONS: Frizzled3 is required to shape the pattern of RBC somas and dendrites, and the structural and functional connectivity between rods and RBCs. Our results highlight novel functions for Fzd3 in regulating retinal development.

Plasticity of motor network and function in the absence of corticospinal projection.

Despite the obvious clinical interest, our understanding of how developmental mechanisms are redeployed during degeneration and regeneration after brain and spinal cord injuries remains quite rudimentary. In animal models of spinal cord injury, although spontaneous regeneration of descending axons is limited, compensation by intact corticospinal axons, descending tracts from the brainstem, and local intrinsic spinal networks all contribute to the recovery of motor function. Here, we investigated spontaneous motor compensation and plasticity that occur in the absence of corticospinal tract, using Celsr3|Emx1 mice in which the corticospinal tract is completely and specifically absent as a consequence of Celsr3 inactivation in the cortex. Mutant mice had no paresis, but displayed hyperactivity in open-field, and a reduction in skilled movements in food pellet manipulation tests. The number of spinal motoneurons was reduced and their terminal arbors at neuromuscular junctions were atrophic, which was reflected in electromyography deficits. Rubrospinal projections, calretinin-positive propriospinal projections, afferent innervation of motoneurons by calretinin-positive segmental interneurons, and terminal ramifications of monoaminergic projections were significantly increased. Contrary to control animals, mutants also developed a severe and persistent disability of forelimb use following the section of the rubrospinal tract at the C4 spinal level. These observations demonstrate for the first time that the congenital absence of the corticospinal tract induces spontaneous plasticity, both at the level of the motor spinal cord and in descending monoaminergic and rubrospinal projections. Such compensatory mechanisms could be recruited in case of brain or spinal cord lesion or degeneration.