Spine Development Research Articles

The small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome.

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, results from silencing of the fragile X mental retardation gene 1 (FMR1). The analyses of FXS patients' brain autopsies revealed an increased density of immature dendritic spines in cortical areas. We hypothesize that the small GTPase Arf6, an actin regulator critical for the development of glutamatergic synapses and dendritic spines, is implicated in FXS. Here, we determined the fraction of active, GTP-bound Arf6 in cortical neuron cultures and synaptoneurosomes from Fmr1 knockout mice, measured actin polymerization in neurons expressing Arf6 mutants with variant GTP- or GDP-binding properties, and recorded hippocampal long-term depression induced by metabotropic glutamate receptors (mGluR-LTD) in acute brain slices. We detected a persistently elevated Arf6 activity, a loss of Arf6 sensitivity to synaptic stimulation and an increased Arf6-dependent dendritic actin polymerization in mature Fmr1 knockout neurons. Similar imbalances in Arf6-GTP levels and actin filament assembly were caused in wild-type neurons by RNAi-mediated depletion of the postsynaptic Arf6 guanylate exchange factors IQSEC1 (BRAG2) or IQSEC2 (BRAG1). Targeted deletion of Iqsec1 in hippocampal neurons of 3-week-old mice interfered with mGluR-LTD in wild-type, but not in Fmr1 knockout mice. Collectively, these data suggest an aberrant Arf6 regulation in Fmr1 knockout neurons with consequences for the actin cytoskeleton, spine morphology, and synaptic plasticity. Moreover, FXS and syndromes caused by genetic variants in IQSEC1 and IQSEC2 share intellectual disabilities and developmental delay as main symptoms. Therefore, dysregulation of Arf6 may contribute to the cognitive impairment in FXS.

Postembryonic screen for mutations affecting spine development in zebrafish

The spine gives structural support for the adult body, protects the spinal cord, and provides muscle attachment for moving through the environment. The development and maturation of the spine and its physiology involve the integration of multiple musculoskeletal tissues including bone, cartilage, and fibrocartilaginous joints, as well as innervation and control by the nervous system. One of the most common disorders of the spine in human is adolescent idiopathic scoliosis (AIS), which is characterized by the onset of an abnormal lateral curvature of the spine of <10° around adolescence, in otherwise healthy children. The genetic basis of AIS is largely unknown. Systematic genome-wide mutagenesis screens for embryonic phenotypes in zebrafish have been instrumental in the understanding of early patterning of embryonic tissues necessary to build and pattern the embryonic spine. However, the mechanisms required for postembryonic maturation and homeostasis of the spine remain poorly understood. Here we report the results from a small-scale forward genetic screen for adult-viable recessive and dominant zebrafish mutations, leading to overt morphological abnormalities of the adult spine. Germline mutations induced with N-ethyl N-nitrosourea (ENU) were transmitted and screened for dominant phenotypes in 1229 F1 animals, and subsequently bred to homozygosity in F3 families; from these, 314 haploid genomes were screened for adult-viable recessive phenotypes affecting general body shape. We cumulatively found 40 adult-viable (3 dominant and 37 recessive) mutations each leading to a defect in the morphogenesis of the spine. The largest phenotypic group displayed larval onset axial curvatures, leading to whole-body scoliosis without vertebral dysplasia in adult fish. Pairwise complementation testing of 16 mutant lines within this phenotypic group revealed at least 9 independent mutant loci. Using massively-parallel whole genome or whole exome sequencing and meiotic mapping we defined the molecular identity of several loci for larval onset whole-body scoliosis in zebrafish. We identified a new mutation in the skolios/kinesin family member 6 (kif6) gene, causing neurodevelopmental and ependymal cilia defects in mouse and zebrafish. We also report multiple recessive alleles of the scospondin and a disintegrin and metalloproteinase with thrombospondin motifs 9 (adamts9) genes, which all display defects in spine morphogenesis. Our results provide evidence of monogenic traits that are essential for normal spine development in zebrafish, that may help to establish new candidate risk loci for spine disorders in humans.

Novel Risk Loci Associated With Genetic Risk for Bipolar Disorder Among Han Chinese Individuals

The genetic basis of bipolar disorder (BD) in Han Chinese individuals is not fully understood. To explore the genetic basis of BD in the Han Chinese population. A genome-wide association study (GWAS), followed by independent replication, was conducted to identify BD risk loci in Han Chinese individuals. Individuals with BD were diagnosed based on DSM-IV criteria and had no history of schizophrenia, mental retardation, or substance dependence; individuals without any personal or family history of mental illnesses, including BD, were included as control participants. In total, discovery samples from 1822 patients and 4650 control participants passed quality control for the GWAS analysis. Replication analyses of samples from 958 patients and 2050 control participants were conducted. Summary statistics from the European Psychiatric Genomics Consortium 2 (PGC2) BD GWAS (20 352 cases and 31 358 controls) were used for the trans-ancestry genetic correlation analysis, polygenetic risk score analysis, and meta-analysis to compare BD genetic risk between Han Chinese and European individuals. The study was performed in February 2020. Single-nucleotide variations with P < 5.00 × 10-8 were considered to show genome-wide significance of statistical association. The Han Chinese discovery GWAS sample included 1822 cases (mean [SD] age, 35.43 [14.12] years; 838 [46%] male) and 4650 controls (mean [SD] age, 27.48 [5.97] years; 2465 [53%] male), and the replication sample included 958 cases (mean [SD] age, 37.82 [15.54] years; 412 [43%] male) and 2050 controls (mean [SD] age, 27.50 [6.00] years; 1189 [58%] male). A novel BD risk locus in Han Chinese individuals was found near the gene encoding transmembrane protein 108 (TMEM108, rs9863544; P = 2.49 × 10-8; odds ratio [OR], 0.650; 95% CI, 0.559-0.756), which is required for dendritic spine development and glutamatergic transmission in the dentate gyrus. Trans-ancestry genetic correlation estimation (ρge = 0.652, SE = 0.106; P = 7.30 × 10-10) and polygenetic risk score analyses (maximum liability-scaled Nagelkerke pseudo R2 = 1.27%; P = 1.30 × 10-19) showed evidence of shared BD genetic risk between Han Chinese and European populations, and meta-analysis identified 2 new GWAS risk loci near VRK2 (rs41335055; P = 4.98 × 10-9; OR, 0.849; 95% CI, 0.804-0.897) and RHEBL1 (rs7969091; P = 3.12 × 10-8; OR, 0.932; 95% CI, 0.909-0.956). This GWAS study identified several loci and genes involved in the heritable risk of BD, providing insights into its genetic architecture and biological basis.

Modulation of dendritic spines by protein phosphatase-1.

Protein phosphatase-1 (PP-1), a highly conserved multifunctional serine/threonine phosphatase, is enriched in dendritic spines where it plays a major role in modulating excitatory synaptic activity. In addition to established functions in spine maturation and development, multi-subunit holoenzyme forms of PP-1 modulate higher-order cognitive functions such learning and memory. Mechanisms involved in regulating PP-1 activity and localization in spines include interactions with neurabin and spinophilin, structurally related synaptic scaffolding proteins associated with the actin cytoskeleton. Since PP-1 is a critical element in synaptic development, signaling, and plasticity, alterations in PP-1 signaling in dendritic spines are implicated in various neurological and psychiatric disorders. The effects of PP-1 depend on its isoform-specific association with regulatory proteins and activation of downstream signaling pathways. Here we review the role of PP-1 and its binding proteins neurabin and spinophilin in both developing and established dendritic spines, as well as some of the disorders that result from its dysregulation.

Diffusive Boundary Layers and Ocean Acidification: Implications for Sea Urchin Settlement and Growth

Chemical changes in the diffusive boundary layer (DBL) generated by photosynthesising macroalgae are expected to play an important role in modulating the effects of ocean acidification (OA) but little is known about the effects on early life stages of marine invertebrates. Larvae that settle to macroalgal surfaces and remain within the DBL will experience pH conditions markedly different from the bulk seawater. We investigated the interactive effects of seawater pH and DBL thickness on settlement and early post-settlement growth of the sea urchin Pseudechinus huttoni, testing whether coralline-algal DBLs act as an environmental buffer to OA. DBL thickness and pH(T) levels above the crustose coralline algal surfaces varied with light availability (with photosynthesis increasing pH to as high as pH 9.0 and respiration reducing pH to as low as pH 7.4 under light and dark conditions respectively), independent of bulk seawater pH (7.5, 7.7 and 8.1). Settlement success of P. huttoni increased over time for all treatments, irrespective of estimated pH in the DBL. Juvenile test growth was similar in all DBL manipulations, showing resilience to variable and low seawater pH. Spine development, however, displayed greater variance with spine growth being negatively affected by reduced seawater pH in the DBL only in the dark treatments. Scanning electron microscopy revealed no observable differences in structural integrity or morphology of the sea urchin spines among pH treatments. Our results suggest that early juvenile stages of Pseudechinus huttoni are well adapted to variable pH regimes in the DBL of macroalgae across a range of bulk seawater pH treatments.

Mutations of CNTNAP1 led to defects in neuronal development.

Mutations of CNTNAP1 were associated with myelination disorders, suggesting the role of CNTNAP1 in myelination processes. Whether CNTNAP1 may have a role in early cortical neuronal development is largely unknown. In this study, we identified 4 compound heterozygous mutations of CNTNAP1 in 2 Chinese families. Using mouse models, we found that CNTNAP1 is highly expressed in neurons and is located predominantly in MAP2+ neurons during the early developmental stage. Importantly, Cntnap1 deficiency results in aberrant dendritic growth and spine development in vitro and in vivo, and it delayed migration of cortical neurons during early development. Finally, we found that the number of parvalbumin+ neurons in the cortex and hippocampus of Cntnap1–/– mice is strikingly increased by P15, suggesting that excitation/inhibition balance is impaired. Together, this evidence elucidates a critical function of CNTNAP1 in cortical development, providing insights underlying molecular and circuit mechanisms of CNTNAP1-related disease.

SUMOylation of spastin promotes the internalization of GluA1 and regulates dendritic spine morphology by targeting microtubule dynamics

Dendritic spines are specialized structures involved in neuronal processes on which excitatory synaptic contact occurs. The microtubule cytoskeleton is vital for maintaining spine morphology and mature synapses. Spastin is related to microtubule-severing proteases and is involved in synaptic bouton formation. However, it is not yet known if spastin can be modified by Small Ubiquitin-like Modifier (SUMO) or how this modification regulates dendritic spines. Spastin was shown to be SUMOylated at K427, and its deSUMOylation promoted microtubule stability. In addition, SUMOylation of spastin was shown to affect signalling pathways associated with long term synaptic depression. SUMOylated spastin promoted the development of dendrites and dendritic spines. Moreover, SUMOylated spastin regulated endocytosis and affected the transport of the AMPA receptor, GluA1. Our findings suggest that SUMOylation of spastin promotes GluA1 internalization and regulates dendritic spine morphology through targeting of microtubule dynamics.

Comparison of life-history parameters and effectiveness in competition with Moina macrocopa between two Keratella tropica morphs

Competition and predation are the two major biotic interactions in zooplankton community. Various rotifer species exhibit polymorphism in lorica and spine morphology in the presence of predators and competitors, which effectively increases their defence competition capacity. This study compared life-history parameters between long-spined morph (LSM) and short-spined morph (SSM) of Keratella tropica at three temperatures. The results showed that both morphs showed significantly higher intrinsic rate of population increase at 25 °C than those at 20 °C and 30 °C. The intrinsic rate of population increase was significantly lower in LSM than SSM at 25 °C and 30 °C, and the net reproductive rate was significantly lower in LSM than SSM at 30 °C. These results suggested that K. tropica had cost on development of long spines, which, however, was dependent on temperature. Moreover, the competition outcome of LSM and SSM with Moina macrocopa were investigated at three densities of Scenedesmus obliquus (0.5 × 106, 1.0 × 106 and 2.0 × 106 cells/mL) and three initial densities of M. macrocopa (0.1, 0.3 and 0.9 ind./mL), revealing that both LSM and SSM populations decreased significantly at all tested algal densities and Moina levels. LSM showed higher population growth rate than SSM at lower algal density (0.5 × 106 cells/mL) and higher Moina densities (0.3 and 0.9 ind./mL), which suggested that LSM could be more effective to defend M. macrocopa. Three-way analysis of variance showed no significant effects of algal density on population growth rate of K. tropica, but interaction between algal density and M. macrocopa density significantly affected its population growth rate.

β‐catenin signaling modulates the tempo of dendritic growth of adult‐born hippocampal neurons

In adult hippocampal neurogenesis, stem/progenitor cells generate dentate granule neurons that contribute to hippocampal plasticity. The establishment of a morphologically defined dendritic arbor is central to the functional integration of adult‐born neurons. We investigated the role of canonical Wnt/β‐catenin signaling in dendritogenesis of adult‐born neurons. We show that canonical Wnt signaling follows a biphasic pattern, with high activity in stem/progenitor cells, attenuation in immature neurons, and reactivation during maturation, and demonstrate that this activity pattern is required for proper dendrite development. Increasing β‐catenin signaling in maturing neurons of young adult mice transiently accelerated dendritic growth, but eventually produced dendritic defects and excessive spine numbers. In middle‐aged mice, in which protracted dendrite and spine development were paralleled by lower canonical Wnt signaling activity, enhancement of β‐catenin signaling restored dendritic growth and spine formation to levels observed in young adult animals. Our data indicate that precise timing and strength of β‐catenin signaling are essential for the correct functional integration of adult‐born neurons and suggest Wnt/β‐catenin signaling as a pathway to ameliorate deficits in adult neurogenesis during aging.

Systematic Quantification of Synapses in Primary Neuronal Culture.

SummaryMost neurological disorders display impaired synaptic connectivity. Hence, modulation of synapse formation may have therapeutic relevance. However, the high density and small size of synapses complicate their quantification. To improve synapse-oriented screens, we analyzed the labeling performance of synapse-targeting antibodies on neuronal cell cultures using segmentation-independent image analysis based on sliding window correlation. When assessing pairwise colocalization, a common readout for mature synapses, overlap was incomplete and confounded by spurious signals. To circumvent this, we implemented a proximity ligation-based approach that only leads to a signal when two markers are sufficiently close. We applied this approach to different marker combinations and demonstrate its utility for detecting synapse density changes in healthy and compromised cultures. Thus, segmentation-independent analysis and exploitation of resident protein proximity increases the sensitivity of synapse quantifications in neuronal cultures and represents a valuable extension to the analytical toolset for in vitro synapse screens.

Subacute cannabidiol alters genome-wide DNA methylation in adult mouse hippocampus.

Use of cannabidiol (CBD), the most abundant non-psychoactive compound found in cannabis (Cannabis sativa), has recently increased as a result of widespread availability of CBD-containing products. CBD is FDA-approved for the treatment of epilepsy and exhibits anxiolytic, antipsychotic, prosocial, and other behavioral effects in animal studies and clinical trials, however, the underlying mechanisms governing these phenotypes are still being elucidated. The epigenome, particularly DNA methylation, is responsive to environmental input and can govern persistent patterns of gene regulation affecting phenotype across the life course. In order to understand the epigenomic activity of cannabidiol exposure in the adult brain, 12-week-old male wild-type a/a Agouti viable yellow (Avy ) mice were exposed to either 20 mg/kg CBD or vehicle daily by oral administration for 14 days. Hippocampal tissue was collected and reduced-representation bisulfite sequencing (RRBS) was performed. Analyses revealed 3,323 differentially methylated loci (DMLs) in CBD-exposed animals with a small skew toward global hypomethylation. Genes for cell adhesion and migration, dendritic spine development, and excitatory postsynaptic potential were found to be enriched in a gene ontology term analysis of DML-containing genes, and disease ontology enrichment revealed an overrepresentation of DMLs in gene sets associated with autism spectrum disorder, schizophrenia, and other phenotypes. These results suggest that the epigenome may be a key substrate for CBD's behavioral effects and provides a wealth of gene regulatory information for further study.

The HD-ZIP IV transcription factor Tril regulates fruit spine density through gene dosage effects in cucumber.

Trichomes and fruit spines are important traits that directly affect the appearance quality and commercial value of cucumber (Cucumis sativus). Tril (Trichome-less), encodes a HD-Zip IV transcription factor that plays a crucial role in the initiation of trichomes and fruit spines, but little is known about the details of the regulatory mechanisms involved. In this study, analysis of tissue expression patterns indicated that Tril is expressed and functions in the early stages of organ initiation and development. Expression of Tril under the control of its own promoter (the TrilPro::Tril-3*flag fragment) could partly rescue the mutant phenotypes of tril, csgl3 (cucumber glabrous 3, an allelic mutant of tril), and fs1 (few spines 1, a fragment substitution in the Tril promoter region), providing further evidence that Tril is responsible for the initiation of trichomes and fruit spines. In lines with dense spine, fs1-type lines, and transgenic lines of different backgrounds containing the TrilPro::Tril-3*flag foreign fragment, spine density increased in conjunction with increases in Tril expression, indicating that Tril has a gene dosage effect on fruit spine density in cucumber. Numerous Spines (NS) is a negative regulatory factor of fruit spine density. Characterization of the molecular and genetic interaction between Tril and NS/ns demonstrated that Tril functions upstream of NS with respect to spine initiation. Overall, our results reveal a novel regulatory mechanism governing the effect of Tril on fruit spine development, and provide a reference for future work on breeding for physical quality in cucumber.

Drebrin expression patterns in patients with refractory temporal lobe epilepsy and hippocampal sclerosis

Drebrins are crucial for synaptic function and dendritic spine development, remodeling, and maintenance. In temporal lobe epilepsy (TLE) patients, a significant hippocampal synaptic reorganization occurs, and synaptic reorganization has been associated with hippocampal hyperexcitability. This study aimed to evaluate, in TLE patients, the hippocampal expression of drebrin using immunohistochemistry with DAS2 or M2F6 antibodies that recognize adult (drebrin A) or adult and embryonic (pan-drebrin) isoforms, respectively. Hippocampal sections from drug-resistant TLE patients with hippocampal sclerosis (HS; TLE, n=33), of whom 31 presented with type 1 HS and two with type 2 HS, and autopsy control cases (n=20) were assayed by immunohistochemistry and evaluated for neuron density, and drebrin A and pan-drebrin expression. Double-labeling immunofluorescences were performed to localize drebrin A-positive spines in dendrites (MAP2), and to evaluate whether drebrin colocalizes with inhibitory (GAD65) and excitatory (VGlut1) presynaptic markers. Compared to controls, TLE patients had increased pan-drebrin in all hippocampal subfields and increased drebrin A-immunopositive area in all hippocampal subfields but CA1. Drebrin-positive spine density followed the same pattern as total drebrin quantification. Confocal microscopy indicated juxtaposition of drebrin-positive spines with VGlut1-positive puncta, but not with GAD65-positive puncta. Drebrin expression in the dentate gyrus of TLE cases was associated negatively with seizure frequency and positively with verbal memory. TLE patients with lower drebrin-immunopositive area in inner molecular layer (IML) than in outer molecular layer (OML) had a lower seizure frequency than those with higher or comparable drebrin-immunopositive area in IML compared with OML. Our results suggest that changes in drebrin-positive spines and drebrin expression in the dentate gyrus of TLE patients are associated with lower seizure frequency, more preserved verbal memory, and a better postsurgical outcome.

Pannexin 1 Regulates Dendritic Protrusion Dynamics in Immature Cortical Neurons.

The integration of neurons into networks relies on the formation of dendritic spines. These specialized structures arise from dynamic filopodia-like dendritic protrusions. It was recently reported that cortical neurons lacking the channel protein pannexin 1 (PANX1) exhibited higher dendritic spine densities. Here, we expanded on those findings to investigate, at an earlier developmental time point (with more abundant dendritic protrusions), whether differences in the properties of dendritic protrusion dynamics could contribute to this previously discovered phenomenon. Using a fluorescent membrane tag (mCherry-CD9-10) to visualize dendritic protrusions in developing neurons [at 10 d in vitro (DIV10)], we confirmed that lack of PANX1 led to higher protrusion density, while transient transfection of Panx1 led to decreased protrusion density. To quantify the impact of PANX1 expression on protrusion formation, elimination, and motility, we used live cell imaging in DIV10 neurons (one frame every 5 s for 10 min). We discovered that at DIV10, loss of PANX1 stabilized protrusions. Notably, re-expression of PANX1 in Panx1 knock-out (KO) neurons resulted in a significant increase in protrusion motility and turnover. In summary, these new data revealed that PANX1 could regulate the development of dendritic spines, in part, by controlling dendritic protrusion dynamics.

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation.

During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human brain disorders such as lissencephaly, autism, schizophrenia, bipolar disorder, depression, mental retardation, Alzheimer’s disease and epilepsy. Several elements of the signaling pathway are known. Core components, such as the Reelin receptors very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), Src family kinases Src and Fyn, and the intracellular adaptor Disabled-1 (Dab1), are common to most but not all Reelin functions. Other downstream effectors are, on the other hand, more specific to defined tasks. Reelin is a large extracellular protein, and some aspects of the signal are regulated by its processing into smaller fragments. Rather than being inhibitory, the processing at two major sites seems to be fulfilling important physiological functions. In this review, I describe the various cellular events regulated by Reelin and attempt to explain the current knowledge on the mechanisms of action. After discussing the shared and distinct elements of the Reelin signaling pathway involved in neuronal migration, dendritic growth, spine development and synaptic plasticity, I briefly outline the data revealing the importance of Reelin in human brain disorders.

Фізична терапія при сколіотичній хворобі І ступеня на поліклінічному етапі

Purpose: analysis of specialized scientific literature on the problem of scoliotic disease of the first degree and the possibilities of physical therapy in the restorative treatment process. Material and methods: an analytical review of domestic and foreign literary sources devoted to the problem of physical therapy of scoliotic disease in the recovery period. The analysis of various methods of physical therapy of the studied pathology was carried out. Results: modern views on spine anatomy, etiology, pathogenesis and development of scoliotic disease are defined. The basic principles of physical therapy program formation for patients with scoliotic disease are highlighted. Conclusions: modern approaches to the occurrence, development, treatment and physical therapy of scoliotic disease of the 1st degree are determined.

TGF-β-Induced Phosphorylation of Usp9X Stabilizes Ankyrin-G and Regulates Dendritic Spine Development and Maintenance

SUMMARYSignaling by the cytokine transforming growth factor β (TGF-β) has been implicated in a multitude of biological functions; however, TGF-β signaling, particularly in the CNS, remains largely unexplored. ANK3 variants (encoding ankyrin-G) are associated with bipolar disorder, intellectual disability, and autism spectrum disorder, while mutations in USP9X, which encodes a deubiquitinase, are associated with X-linked intellectual disability and autism in humans. Here, we show that TGF-β signaling promotes Usp9X phosphorylation, which enhances its interaction with ankyrin-G and stabilizes ankyrin-G in spines, leading to spine enlargement. Using in situ proximity ligation combined with structured illumination superresolution microscopy, we characterize the postsynaptic spatial organization of phosphorylation-dependent regulation of Usp9X/ankyrin-G interactions in dendrites and its quantitative relationship with spine morphology and number. These data reveal a cytokine-mediated mechanism regulating protein stability in spines and suggest a role for deubiquitination and TGF-β signaling in neurodevelopmental disorder pathogenesis and treatment.

Functional analysis and signaling pathway enrichment analysis of genes associated with Alzheimer’s disease and Parkinson’s disease

We identified significant functions of susceptibility-genes and performed an analysis of pathway enrichment for Alzheimer’s disease, Parkinson’s disease and for both of them. Genes were extracted from a Catalog of Published Genome-Wide Association Studies (GWAS). We uploaded genes into Cytoscape version 3.2.1. ClueGO plugin was used for functional and pathway enrichment analysis of genes based on the hypergeometric test. Two databases, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and REACTOME, were selected for analysis. The identified susceptibility genes are involved in the synthesis regulation and accumulation of toxic proteins, β -amyloid and α -synuclein, and lead to apoptosis of neurons. We have defined 14 shared functions: collagen catabolic process, cellular response to retinoic acid, regulation of calcium-mediated signaling, negative regulation of cell projection organization, negative regulation of neuron projection development, glial cell activation, microglial cell activation, macrophage activation, regulation of cholesterol metabolism, clathrin-mediated endocytosis, regulation of protein oligomerization, regulation of dendritic spine development, kinesin binding and clathrin binding. Also, we have defined 3 shared signaling pathways: trans-Golgi Network Vesicle Budding, Clathrin derived vesicle budding, Intestinal immune network for IgA production. These pathways contain genes susceptible to Alzheimer’s disease and Parkinson’s disease. The results suggest the metabolic, neuronal and immunological factors participate in the development of Parkinson’s disease and Alzheimer’s disease.

Mesenchymal Stem Cell-Specific and Preosteoblast-Specific Ablation of TSC1 in Mice Lead to Severe and Slight Spinal Dysplasia, Respectively.

Background TSC1-related signaling plays a pivotal role in intramembranous and endochondral ossification processes during skeletogenesis. This study was aimed at determining the significance of the TSC1 gene at different stages of spinal development. Materials and Methods. TSC1-floxed mice (TSC1flox/flox) were crossed with Prrx1-Cre or BGLAP-Cre transgenic mice or mesenchymal stem cell- and osteoblast-specific TSC1-deficient mice, respectively. Somatic and vertebral differences between WT and Prrx1-TSC1 null mice were examined at 4 weeks after birth. Results No apparent body size abnormalities were apparent in newborn and 4-week- to 2-month-old mice with BGLAP-Cre driver-depleted TSC1. Vertebral and intervertebral discs displayed strong dysplasia in Prrx1-TSC1 null mice. In contrast, vertebrae were only slightly affected, and intervertebral discs from skeletal preparations displayed no apparent changes in BGLAP-TSC1 null mice. Conclusion Our data suggest that the TSC1 gene is crucial for endochondral ossification during postnatal spine development but plays discriminative roles at different stages. Mesenchymal stem cell-specific ablation of TSC1 led to severe spinal dysplasia at early stages of endochondral ossification while osteoblast-specific deletion of TSC1 affected vertebrae slightly and had no detectable effects on intervertebral discs.

MRI study on the normal fetal development of cervical, thoracic and lumbar spines in specimens

Objective To assess the change rules of fetal cervical, thoracic and lumbar spinal volume and centrum volume with gestational ages. Methods The 3.0 T MRI was performed on 55 fetal specimens ranging from 17 to 42 gestational weeks with sequence of three dimensional T2WI. Among 55 samples, 20 samples were obtained from spontaneous abortion of pregnant women and 35 samples were obtained from induced labor of mothers due to serious diseases. The fetal specimen was derived from sectional imaging anatomy research institute of the medical school of Shandong University. No spinal abnormalities were found on CT scans. The cervical, thoracic and lumbar spinal volume was obtained by delineating the vertebral body contour on the reconstructed cross-sectional image with the OsiriX software (www.osirix-viewer.com). And the volume of the cervical, thoracic and lumbar spine was divided by the number of the vertebral bodies to obtain the centrum unit volume. Five lumbar vertebral bodies were measured one by one. Regression analysis was made between the volume of cervical, thoracic and lumbar spine and gestational weeks, and between the volume of lumbar vertebral bodies and gestational weeks to analyze the growth rule of spine. Results (1) The cervical, thoracic and lumbar spine volume increased linearly with gestational ages, and the linear regression equation was as follows: cervical spine volume (mm3) =-1 260.937+81.235×gestational week (R2=0.974, P<0.05), thoracic spine volume (mm3) =-5 933.521+347.503×gestational week (R2=0.972,P<0.05), lumbar spine volume (mm3) =-5 130.912+294.473×gestational week (R2=0.976,P<0.05). (2) The order from large to small of fetal spinal growth rate was thoracic, lumbar and cervical segment. Within the same gestational age, the order from large to small of spinal volume was thoracic, lumbar and cervical segment. The order from large to small of centrum unit volume growth rate was lumbar, thoracic and cervical vertebrae. (3) The volume of each lumbar vertebral body also increased linearly with gestational age. Conclusion The cervical, thoracic and lumbar volume show a good correlation with the gestational weeks in the second and third trimester fatal specimens, and the growth rate of different segments is different. Key words: Fetus; Spine; Bone development; Magnetic resonance imaging