• Neurogenesis/physiology
• Spinal Cord/embryology
• Spinal Cord/cytology
• Spinal Cord/growth & development
• Animals
• Humans
• Neural Tube/embryology
• Neural Tube/cytology
• Neural Tube/physiology
• Neural Stem Cells/physiology
• Neural Stem Cells/cytology

• Apoptosis
• brain disorders
• inducers
• neural stem cells
• neurodegenerative diseases
• therapeutic approaches

• Apoptosis
• Chick neural tube
• Dyrk1B
• Motor neurons
• Neuronal subtypes
• Ventral progenitor domains

• Animals
• Hedgehog Proteins/genetics
• Apoptosis
• Chickens
• Interneurons
• Motor Neurons

• MIS 5002486 KRHPIS II-«Action Strategic Development on the Research and Technological Sector»
• NOSTOS Foundation
• Hellenic Pasteur Institute

• Sonic Hedgehog
• cell survival
• chick
• helicase
• neural development

• Neural Tube
• Chromatin Assembly and Disassembly
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Signal Transduction/physiology
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Neural Stem Cells

• 19H04781 Japan Society for the Promotion of Science
• 20H03263 Japan Society for the Promotion of Science

• Ethanol
• FAS
• Hedgehog
• Retinoic acid
• Sea urchins
• Timing

• EED
• EED-Gli3-Gli1 regulatory axis
• PRC2
• cortical development
• hedgehog signaling
• neurogenesis

Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by triplication of Chromosome 21. Gene triplication may compromise different body functions but invariably impairs intellectual abilities starting from infancy. Moreover, after the fourth decade of life people with DS are likely to develop Alzheimer’s disease. Neurogenesis impairment during fetal life stages and dendritic pathology emerging in early infancy are thought to be key determinants of alterations in brain functioning in DS. Although the progressive improvement in medical care has led to a notable increase in life expectancy for people with DS, there are currently no treatments for intellectual disability. Increasing evidence in mouse models of DS reveals that pharmacological interventions in the embryonic and neonatal periods may greatly benefit brain development and cognitive performance. The most striking results have been obtained with pharmacotherapies during embryonic life stages, indicating that it is possible to pharmacologically rescue the severe neurodevelopmental defects linked to the trisomic condition. These findings provide hope that similar benefits may be possible for people with DS. This review summarizes current knowledge regarding (i) the scope and timeline of neurogenesis (and dendritic) alterations in DS, in order to delineate suitable windows for treatment; (ii) the role of triplicated genes that are most likely to be the key determinants of these alterations, in order to highlight possible therapeutic targets; and (iii) prenatal and neonatal treatments that have proved to be effective in mouse models, in order to rationalize the choice of treatment for human application. Based on this body of evidence we will discuss prospects and challenges for fetal therapy in individuals with DS as a potential means of drastically counteracting the deleterious effects of gene triplication.

• Università di Bologna

SCL/TAL1 Interrupting locus (STIL) is a ciliary-related gene involved in regulating the cell cycle and duplication of centrioles in dividing cells. STIL has been found disordered in multiple cancers and driven carcinogenesis. However, the molecular mechanisms and biological functions of STIL in cancers remain ambiguous. Here, we systematically analyzed the genetic alterations, molecular mechanisms, and clinical relevance of STIL across >10,000 samples representing 33 cancer types in The Cancer Genome Atlas (TCGA) dataset. We found that STIL expression is up-regulated in most cancer types compared with their adjacent normal tissues. The expression dysregulation of STIL was affected by copy number variation, mutation, and DNA methylation. High STIL expression was associated with worse outcomes and promoted the progression of cancers. Gene Ontology (GO) enrichment analysis and Gene Set Variation Analysis (GSVA) further revealed that STIL is involved in cell cycle progression, Mitotic spindle, G2M checkpoint, and E2F targets pathways across cancer types. STIL expression was negatively correlated with multiple genes taking part in ciliogenesis and was positively correlated with several genes which participated with centrosomal duplication or cilia degradation. Moreover, STIL silencing could promote primary cilia formation and inhibit cell cycle protein expression in prostate and kidney cancer cell lines. The phenotype and protein expression alteration due to STIL silencing could be reversed by IFT88 silencing in cancer cells. These results revealed that STIL could regulate the cell cycle through primary cilia in tumor cells. In summary, our results revealed the importance of STIL in cancers. Targeting STIL might be a novel therapeutic approach for cancers.

• National Natural Science Foundation of China
• Tianjin Research Program of Application Foundation and Advanced Technology of China

• Dopamine
• GABA
• Neuropsychiatric disorders
• Neurotransmitters
• Oxytocin
• Serotonin
• Sexual fluidity
• Sexual orientation

• Animals
• Brain
• Female
• Gonadal Steroid Hormones
• Hormones
• Humans
• Male
• Neurotransmitter Agents
• Pregnancy
• Sexual Behavior

To ensure the formation of a properly patterned embryo, multiple processes must operate harmoniously at sequential phases of development. This is implemented by mutual interactions between cells and tissues that together regulate the segregation and specification of cells, their growth and morphogenesis. The formation of the spinal cord and paraxial mesoderm derivatives exquisitely illustrate these processes. Following early gastrulation, while the vertebrate body elongates, a population of bipotent neuromesodermal progenitors resident in the posterior region of the embryo generate both neural and mesodermal lineages. At later stages, the somitic mesoderm regulates aspects of neural patterning and differentiation of both central and peripheral neural progenitors. Reciprocally, neural precursors influence the paraxial mesoderm to regulate somite-derived myogenesis and additional processes by distinct mechanisms. Central to this crosstalk is the activity of the axial notochord, which, via sonic hedgehog signaling, plays pivotal roles in neural, skeletal muscle and cartilage ontogeny. Here, we discuss the cellular and molecular basis underlying this complex developmental plan, with a focus on the logic of sonic hedgehog activities in the coordination of the neural-mesodermal axis.

• cell differentiation
• dermomyotome
• floor plate
• lateral plate mesoderm
• motoneurons
• muscle
• neural tube
• notochord
• sclerotome
• somite

• Cognitive function
• Down Syndrome
• Hyperactivity
• Sonic hedgehog
• TRE-hShh
• Ts65Dn

• Animals
• Cerebellum/metabolism
• Cognition/physiology
• Disease Models, Animal
• Down Syndrome/genetics
• Down Syndrome/metabolism
• Down Syndrome/physiopathology
• Gene Knock-In Techniques
• Hedgehog Proteins/genetics
• Hippocampus/metabolism
• Humans
• Learning/physiology
• Locomotion/genetics
• Memory/physiology
• Mice
• Mice, Transgenic
• Prosencephalon/metabolism
• Spatial Processing/physiology
• Zinc Finger Protein GLI1/metabolism

• P30 AG066507 NIA NIH HHS
• R21HD098540 NIH HHS
• R01 HD038384 NICHD NIH HHS
• R01HD038384 NIH HHS
• R21 HD098540 NICHD NIH HHS
• national institutes of health

• chick
• differentiation
• neural development

• Autism
• apoptosis
• neurogenesis
• propionic acid
• purmorphamine
• smo-shh signaling

• Arid1a
• Hh signaling
• Plagl1
• cell cycle
• stem/progenitor cells

• Animals
• Cell Cycle Checkpoints
• Cell Cycle Proteins/metabolism
• Cell Differentiation
• Cell Lineage
• DNA-Binding Proteins/deficiency
• DNA-Binding Proteins/metabolism
• Down-Regulation
• Genes, Tumor Suppressor
• Hedgehog Proteins/metabolism
• Mice, Inbred C57BL
• Mice, Transgenic
• Molar/metabolism
• Odontoblasts/cytology
• Odontoblasts/metabolism
• Protein Binding
• Signal Transduction
• Stem Cells/cytology
• Stem Cells/metabolism
• Tooth Root/cytology
• Tooth Root/growth & development
• Transcription Factors/deficiency
• Transcription Factors/metabolism
• Transcription, Genetic
• Up-Regulation
• Zinc Finger Protein GLI1/genetics
• Zinc Finger Protein GLI1/metabolism
• Mice

• R01 DE012711 NIDCR NIH HHS
• R01 DE022503 NIDCR NIH HHS
• R21 DE028617 NIDCR NIH HHS
• U01 DE028729 NIDCR NIH HHS

Chronic myeloid leukemia (CML) patients with complex chromosomal translocations as well as non-compliant CML patients often demonstrate short-lived responses and poor outcomes on the current therapeutic regimes using Imatinib and its variants. It has been derived so far that leukemic stem cells (LSCs) are responsible for Imatinib resistance and CML progression. Sonic hedgehog (Shh) signaling has been implicated in proliferation of this Imatinib-resistant CD34(+) LSCs. Our work here identifies the molecular mechanism of Shh-mediated mutation-independent Imatinib resistance that is most relevant for treating CML-variants and non-compliant patients. Our results elucidate that while Shh can impart stemness, it also upregulates expression of anti-apoptotic protein—Bcl2. It is the upregulation of Bcl2 that is involved in conferring Imatinib resistance to the CD34(+) LSCs. Sub-toxic doses of Bcl2 inhibitor or Shh inhibitor (<<IC50), when used as adjuvants along with Imatinib, can re-sensitize Shh signaling cells to Imatinib. Our work here highlights the need to molecularly stratify CML patients and implement combinatorial therapy to overcome the current limitations and improve outcomes in CML.

• Sonic Hedgehog
• developmental biology
• growth
• mathematical modelling
• morphogenesis
• patterning

• Animals
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Mitogens/genetics
• Models, Biological
• Morphogenesis/genetics
• Vertebrates/embryology
• Vertebrates/growth & development

• Wellcome Trust
• 212247/Z/18/Z Wellcome Trust
• Engineering and Physical Sciences Research Council

• BMP
• Dermomyotome
• Dorso-ventral patterning
• Hb9
• Motoneurons
• Myotome
• Neural tube
• Nkx
• Olig2
• Paraxial mesoderm
• Pax7
• Retinoic acid
• Somite

• Animals
• Body Patterning/genetics
• Cell Differentiation/genetics
• Chick Embryo
• Gene Expression Regulation, Developmental
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Mesoderm/metabolism
• Motor Neurons/metabolism
• Neural Plate/metabolism
• Neural Tube/embryology
• Neural Tube/metabolism
• Neurogenesis/genetics
• Neurulation/genetics
• Notochord/metabolism
• Patched-1 Receptor/metabolism
• Quail/embryology
• Signal Transduction/genetics
• Transfection

• Israel Science Foundation

Neuronal development is a complex multistep process that shapes neurons by progressing though several typical stages, including axon outgrowth, dendrite formation, and synaptogenesis. Knowledge of the mechanisms of neuronal development is mostly derived from the study of animal models. Advances in stem cell technology now enable us to generate neurons from human induced pluripotent stem cells (iPSCs). Here we provide a mass spectrometry-based quantitative proteomic signature of human iPSC-derived neurons, i.e., iPSC-derived induced glutamatergic neurons and iPSC-derived motor neurons, throughout neuronal differentiation. Tandem mass tag 10-plex labeling was carried out to perform proteomic profiling of cells at different time points. Our analysis reveals significant expression changes (FDR < 0.001) of several key proteins during the differentiation process, e.g., proteins involved in the Wnt and Notch signaling pathways. Overall, our data provide a rich resource of information on protein expression during human iPSC neuron differentiation.

• TMT 10-plex
• human development
• iPSC
• mass spectrometry
• neuronal development
• neuronal differentiation
• neuroproteomics
• proteome
• quantitative proteomics
• tandem mass tags

All vertebrates have a spinal cord with dimensions and shape specific to their species. Yet how species‐specific organ size and shape are achieved is a fundamental unresolved question in biology. The formation and sculpting of organs begins during embryonic development. As it develops, the spinal cord extends in anterior–posterior direction in synchrony with the overall growth of the body. The dorsoventral (DV) and apicobasal lengths of the spinal cord neuroepithelium also change, while at the same time a characteristic pattern of neural progenitor subtypes along the DV axis is established and elaborated. At the basis of these changes in tissue size and shape are biophysical determinants, such as the change in cell number, cell size and shape, and anisotropic tissue growth. These processes are controlled by global tissue‐scale regulators, such as morphogen signaling gradients as well as mechanical forces. Current challenges in the field are to uncover how these tissue‐scale regulatory mechanisms are translated to the cellular and molecular level, and how regulation of distinct cellular processes gives rise to an overall defined size. Addressing these questions will help not only to achieve a better understanding of how size is controlled, but also of how tissue size is coordinated with the specification of pattern.

This article is categorized under:

Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing

• morphogen
• neural tube
• pattern scaling
• spinal cord
• tissue size

The neural tube is composed of a number of neural progenitors and postmitotic neurons distributed in a quantitatively and spatially precise manner. The floor plate, located in the ventral-most region of the neural tube, has a lot of unique characteristics, including a low cell proliferation rate. The mechanisms by which this region-specific proliferation rate is regulated remain elusive. Here we show that the activity of the mTOR signaling pathway, which regulates the proliferation of the neural progenitor cells, is significantly lower in the floor plate than in other domains of the embryonic neural tube. We identified the forkhead-type transcription factor FoxA2 as a negative regulator of mTOR signaling in the floor plate, and showed that FoxA2 transcriptionally induces the expression of the E3 ubiquitin ligase RNF152, which together with its substrate RagA, regulates cell proliferation via the mTOR pathway. Silencing of RNF152 led to the aberrant upregulation of the mTOR signal and aberrant cell division in the floor plate. Taken together, the present findings suggest that floor plate cell number is controlled by the negative regulation of mTOR signaling through the activity of FoxA2 and its downstream effector RNF152.

• cell proliferation
• chick
• floor plate
• mTOR
• neural tube

Sonic hedgehog (SHH) is a vertebrate homologue of the secreted Drosophila protein hedgehog and is expressed by the notochord and floor plate in the developing spinal cord. Sonic hedgehog provides signals relevant for positional information, cell proliferation and possibly cell survival, depending on the time and location of expression. Although the role of SHH in providing positional information in the neural tube has been experimentally proven, the underlying mechanism remains unclear. In this study, in ovo electroporation was employed in the chicken spinal cord during chicken embryo development. Electroporation was conducted at stage 17 (E2.5), after electroporation the embryos were continued incubating to stage 28 (E6) for sampling, tissue fixation with 4% paraformaldehyde and frozen sectioning. Sonic hedgehog and related protein expressions were detected by in situ hybridization and fluorescence immunohistochemistry and the results were analysed after microphotography. Our results indicate that the ectopic expression of SHH leads to ventralization in the spinal cord during chicken embryonic development by inducing abnormalities in the structure of the motor column and motor neuron integration. In addition, ectopic SHH expression inhibits the expression of dorsal transcription factors and commissural axon projections. The correct location of SHH expression is vital to the formation of the motor column. Ectopic expression of SHH in the spinal cord not only affects the positioning of motor neurons, but also induces abnormalities in the structure of the motor column. It leads to ventralization in the spinal cord, resulting in the formation of more ventral neurons forming during neuronal formation.

• chicken embryo
• in ovo electroporation
• motor neuron
• sonic hedgehog
• spinal cord

• Corticogenesis
• Critical period
• Optic tectum
• Patterning
• Sensitive period

• anti-inflammation
• anti-oxidation
• autophagy
• neurodegenerative diseases
• neurogenesis
• sonic hedgehog

• Adult
• Animals
• Antioxidants/metabolism
• Autophagy
• Hedgehog Proteins/metabolism
• Humans
• Nervous System Diseases/metabolism
• Nervous System Diseases/pathology
• Neurogenesis
• Signal Transduction

Skeletal myogenesis serves as a paradigm to investigate the molecular mechanisms underlying exquisitely regulated cell fate decisions in developing embryos. The evolutionarily conserved miR-133 family of microRNAs is expressed in the myogenic lineage, but how it acts remains incompletely understood. Here, we performed genome-wide differential transcriptomics of miR-133 knockdown (KD) embryonic somites, the source of vertebrate skeletal muscle. These analyses, performed in chick embryos, revealed extensive downregulation of Sonic hedgehog (Shh) pathway components: patched receptors, Hedgehog interacting protein and the transcriptional activator Gli1. By contrast, Gli3, a transcriptional repressor, was de-repressed and confirmed as a direct miR-133 target. Phenotypically, miR-133 KD impaired myotome formation and growth by disrupting proliferation, extracellular matrix deposition and epithelialization. Together, these observations suggest that miR-133-mediated Gli3 silencing is crucial for embryonic myogenesis. Consistent with this idea, we found that activation of Shh signalling by either purmorphamine, or KD of Gli3 by antisense morpholino, rescued the miR-133 KD phenotype. Thus, we identify a novel Shh/myogenic regulatory factor/miR-133/Gli3 axis that connects epithelial morphogenesis with myogenic fate specification.

Summary: Here, using chick embryos, we showed that post-transcriptional silencing of the Gli3 repressor by miR-133 is required to stably establish the myogenic programme in early somites.

• Basement membrane
• Chick embryo
• Gli3
• Somite myogenesis
• Sonic hedgehog signalling
• miR-133

• Humans
• Intracellular Signaling Peptides and Proteins/genetics
• Intracellular Signaling Peptides and Proteins/metabolism
• Microcephaly/genetics
• Neoplasms/genetics

• APP, RCAN1, OLIG1/2
• Apoptotic cell death
• Astrogliogenesis
• Brain development
• DYRK1A
• Down syndrome
• Neurogenesis

• Animals
• Down Syndrome/metabolism
• Down Syndrome/pathology
• Humans
• Nervous System Malformations/metabolism
• Nervous System Malformations/pathology
• Neural Stem Cells/metabolism
• Neural Stem Cells/pathology
• Neurogenesis

• 5-HT neuron
• Sfrp1
• Shh
• Wnt/PCP signaling pathway
• Wnt5a

• Animals
• Axon Guidance/drug effects
• Axon Guidance/genetics
• Cells, Cultured
• Electroporation
• Embryo, Mammalian
• Gene Expression Regulation, Developmental/drug effects
• Gene Expression Regulation, Developmental/genetics
• Green Fluorescent Proteins/genetics
• Green Fluorescent Proteins/metabolism
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Immunoprecipitation
• Intercellular Signaling Peptides and Proteins/metabolism
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins/antagonists & inhibitors
• Membrane Proteins/metabolism
• Mice
• Morpholines/pharmacology
• Patched-1 Receptor/metabolism
• Proteins/genetics
• Proteins/metabolism
• Pyridines/pharmacology
• Rhombencephalon/cytology
• Serotonergic Neurons/cytology
• Serotonergic Neurons/drug effects
• Serotonin/metabolism
• Wnt-5a Protein/genetics
• Wnt-5a Protein/metabolism

The differentiated cell types of the epithelial and mesenchymal tissue compartments of the mature ureter of the mouse arise in a precise temporal and spatial sequence from uncommitted precursor cells of the distal ureteric bud epithelium and its surrounding mesenchyme. Previous genetic efforts identified a member of the Hedgehog (HH) family of secreted proteins, Sonic hedgehog (SHH) as a crucial epithelial signal for growth and differentiation of the ureteric mesenchyme. Here, we used conditional loss- and gain-of-function experiments of the unique HH signal transducer Smoothened (SMO) to further characterize the cellular functions and unravel the effector genes of HH signaling in ureter development. We showed that HH signaling is not only required for proliferation and SMC differentiation of cells of the inner mesenchymal region but also for survival of cells of the outer mesenchymal region, and for epithelial proliferation and differentiation. We identified the Forkhead transcription factor gene Foxf1 as a target of HH signaling in the ureteric mesenchyme. Expression of a repressor version of FOXF1 in this tissue completely recapitulated the mesenchymal and epithelial proliferation and differentiation defects associated with loss of HH signaling while re-expression of a wildtype version of FOXF1 in the inner mesenchymal layer restored these cellular programs when HH signaling was inhibited. We further showed that expression of Bmp4 in the ureteric mesenchyme depends on HH signaling and Foxf1, and that exogenous BMP4 rescued cell proliferation and epithelial differentiation in ureters with abrogated HH signaling or FOXF1 function. We conclude that SHH uses a FOXF1-BMP4 module to coordinate the cellular programs for ureter elongation and differentiation, and suggest that deregulation of this signaling axis occurs in human congenital anomalies of the kidney and urinary tract (CAKUT).

The mammalian ureter is a simple tube with a specialized multi-layered epithelium, the urothelium, and a surrounding coat of fibroblasts and peristaltically active smooth muscle cells. Besides its important function in urinary drainage, the ureter represents a simple model system to study epithelial and mesenchymal tissue interactions in organ development. The differentiated cell types of the ureter coordinately arise from precursor cells of the distal ureteric bud and its surrounding mesenchyme. How their survival, growth and differentiation is regulated and coordinated within and between the epithelial and mesenchymal tissue compartments is largely unknown. Previous work identified Sonic hedgehog (SHH) as a crucial epithelial signal for growth and differentiation of the ureteric mesenchyme, but the entirety of the cellular functions and the molecular mediators of its mesenchymal signaling pathway have remained obscure. Here we showed that epithelial SHH acts in a paracrine fashion onto the ureteric mesenchyme to activate a FOXF1-BMP4 regulatory module that directs growth and differentiation of both ureteric tissue compartments. HH signaling additionally acts in outer mesenchymal cells as a survival factor. Thus, SHH is an epithelial signal that coordinates various cellular programs in early ureter development.

• Animals
• Bone Morphogenetic Protein 4/genetics
• Bone Morphogenetic Protein 4/metabolism
• Cell Differentiation
• Cell Proliferation
• Disease Models, Animal
• Epithelium/embryology
• Epithelium/metabolism
• Female
• Forkhead Transcription Factors/genetics
• Forkhead Transcription Factors/metabolism
• Gene Expression Regulation, Developmental
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Image Processing, Computer-Assisted
• Male
• Mesoderm/embryology
• Mesoderm/metabolism
• Mice
• Microarray Analysis
• Organogenesis/genetics
• Reproducibility of Results
• Signal Transduction
• Smoothened Receptor/genetics
• Smoothened Receptor/metabolism
• Ureter/embryology
• Ureter/metabolism

• Deutsche Forschungsgemeinschaft

• Atg7
• Autophagy
• Cell cycle
• Neural crest

• Sonic Hedgehog
• amniotes
• glial cells
• lateral floor plate
• medial floor plate
• neural tube patterning
• neurons
• notochord
• zebrafish

As reflected by the term morphogen, molecules such as Shh and Wnts were identified based on their role in early development when they instruct precursor cells to adopt a specific cell fate. Only much later were they implicated in neural circuit formation. Both in vitro and in vivo studies indicated that morphogens direct axons during their navigation through the developing nervous system. Today, the best understood role of Shh and Wnt in axon guidance is their effect on commissural axons in the spinal cord. Shh was shown to affect commissural axons both directly and indirectly via its effect on Wnt signaling. In fact, throughout neural circuit formation there is cross-talk and collaboration of Shh and Wnt signaling. Thus, although the focus of this review is on the role of Shh in neural circuit formation, a separation from Wnt signaling is not possible.

• axon guidance
• commissural axons
• midline crossing
• synaptogenesis

Sonic hedgehog (Shh) signaling occurs concurrently with the many processes that constitute nervous system development. Although Shh is mostly known for its proliferative and morphogenic action through its effects on neural stem cells and progenitors, it also contributes to neuronal differentiation, axonal pathfinding and synapse formation and function. To participate in these diverse events, Shh signaling manifests differently depending on the maturational state of the responsive cell, on the other signaling pathways regulating neural cell function and the environmental cues that surround target cells. Shh signaling is particularly dynamic in the nervous system, ranging from canonical transcription-dependent, to non-canonical and localized to axonal growth cones. Here, we review the variety of Shh functions in the developing nervous system and their consequences for neurodevelopmental diseases and neural regeneration, with particular emphasis on the signaling mechanisms underlying Shh action.

• calcium signaling
• medulloblastoma
• neural regeneration
• neurodevelopmental disorders
• neuronal differentiation
• non-canonical Sonic hedgehog signaling
• synapse formation

• Drosophila
• IRX
• chick embryo
• iroquois
• limb bud
• morphogen
• mouse
• neural tube
• proliferation
• temporal adaptation
• zebrafish

• MC_PC_13052 Medical Research Council

• Animals
• Hedgehog Proteins/metabolism
• Hippocampus/metabolism
• Humans
• Neuronal Plasticity/physiology
• Signal Transduction

• ZIA AG000314-16 Intramural NIH HHS
• ZIA AG000317-16 Intramural NIH HHS
• ZIC DC000081 Intramural NIH HHS

The eutherian X-chromosome specific family of Armcx genes has been described as originating by retrotransposition from Armc10/SVH, a single Arm-containing somatic gene. Armcx3 and Armc10/SVH are characterized by high expression in the central nervous system and they play an important role in the regulation of mitochondrial distribution and transport in neurons. In addition, Armcx/Arm10 genes have several Armadillo repeats in their sequence. In this study we address the potential role of this gene family in neural development by using the chick neural tube as a model. We show that Armc10/SVH is expressed in the chicken spinal cord, and knocking-down Armc10/SVH by sh-RNAi electroporation in spinal cord reduces proliferation of neural precursor cells (NPCs). Moreover, we analyzed the effects of murine Armcx3 and Armc10 overexpression, showing that both proteins regulate progenitor proliferation, while Armcx3 overexpression also specifically controls neural maturation. We show that the phenotypes found following Armcx3 overexpression require its mitochondrial localization, suggesting a novel link between mitochondrial dynamics and regulation of neural development. Furthermore, we found that both Armcx3 and Armc10 may act as inhibitors of Wnt-β-catenin signaling. Our results highlight both common and differential functions of Armcx/Armc10 genes in neural development in the spinal cord.

• Armc10 gene
• Armcx gene cluster
• mitochondria
• neuronal differentiation
• progenitor proliferation
• spinal cord development

Glioblastoma multiforme (GBM), the literal apogee on the hierarchy of malignant brain tumors, remains one of the greatest therapeutic challenges in oncology and medicine. Historically this may be contextualized in the fact that the medical and scientific communities have had a very elementary understanding of its intricate and complex pathophysiology. The last 10-15 years have yielded a number of studies that have elucidated much of the molecular and genetic complexities of GBM that underlie its pathogenesis. Excitingly, some of these discovered genetic mutations and molecular profiles in GBM have demonstrated value in prognostication and utility in predicting response to treatment. Despite this, however, treatment options for patients have remained somewhat limited. These treatment options are expected to expand with the availability of new data and with the transition of novel treatment modalities from animal to human studies. This paper will have a threefold objective: provide an overview of the traditional paradigm in understanding and treating GBM, describe recent discoveries in the molecular pathogenesis of GBM against this historical backdrop, and acquaint the reader with new treatment modalities that hold significant therapeutic potential for patients.

• Molecular pathogenesis
• Temozolomide
• Glioblastoma multiforme
• Treatment resistance
• Hypoxia
• Recurrent glioblastoma multiforme
• Bevacizumab

• Adenylyl cyclase
• Cerebellar granular neuron precursor
• Hedgehog pathway
• Primary cilium

• Animals
• Avian Proteins/genetics
• Avian Proteins/metabolism
• Body Patterning/physiology
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Chick Embryo
• Chickens
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Heparitin Sulfate/genetics
• Heparitin Sulfate/metabolism
• Neural Stem Cells/cytology
• Neural Stem Cells/metabolism
• Signal Transduction/physiology

• 1F31 NS081806 NINDS NIH HHS
• R01 DC014428 NIDCD NIH HHS
• P30 CA046592 NCI NIH HHS
• T32 GM007863 NIGMS NIH HHS
• 14414 Cancer Research UK
• R21 CA167122 NCI NIH HHS
• T32 GM007315 NIGMS NIH HHS
• F31 NS081806 NINDS NIH HHS
• 090532 Wellcome Trust

• AJ, adherens junction
• EC, extracellular
• Fox, forkhead box
• Frz, frizzled
• GFAP, glial fibrillary acidic protein
• GSK3β, glycogen synthase kinase 3β
• Hes, hairly/enhancer of split
• Hh, hedgehog
• IP, intermediate progenitor
• KO, knockout
• LEF, lymphocyte enhancer factor
• N-cadherin
• NPC, neural progenitor cell
• Par, partition defective complex protein
• Ptc, Pached
• Smo, smoothened
• Sox2, sry (sex determining region Y)-box containing gene 2
• TA cell, transient amplifying cell; ZO-1, Zonula Occludens-1.
• TCF, T-cell factor
• aPKC, atypical protein kinase C
• adherens junction
• apico-basal polarity
• iPSC, induced pluripotent stem cell
• neural progenitor cells
• ngn2, neurogenin 2
• shRNA, short hairpin RNA
• β-catenin

• BarH
• Sonic Hedgehog
• Wnt
• development
• diencephalon
• organizer

This is the first study of the role of BRE in embryonic development using early chick embryos. BRE is expressed in the developing neural tube, neural crest cells, and somites. BRE thus plays an important role in regulating neurogenesis and indirectly somitogenesis during early chick embryo development.

The brain and reproductive expression (BRE) gene is expressed in numerous adult tissues and especially in the nervous and reproductive systems. However, little is known about BRE expression in the developing embryo or about its role in embryonic development. In this study, we used in situ hybridization to reveal the spatiotemporal expression pattern for BRE in chick embryo during development. To determine the importance of BRE in neurogenesis, we overexpressed BRE and also silenced BRE expression specifically in the neural tube. We established that overexpressing BRE in the neural tube indirectly accelerated Pax7⁺ somite development and directly increased HNK-1⁺ neural crest cell (NCC) migration and TuJ-1⁺ neurite outgrowth. These altered morphogenetic processes were associated with changes in the cell cycle of NCCs and neural tube cells. The inverse effect was obtained when BRE expression was silenced in the neural tube. We also determined that BMP4 and Shh expression in the neural tube was affected by misexpression of BRE. This provides a possible mechanism for how altering BRE expression was able to affect somitogenesis, neurogenesis, and NCC migration. In summary, our results demonstrate that BRE plays an important role in regulating neurogenesis and indirectly somite differentiation during early chick embryo development.

• 2,5-Hexanedione
• Angiogenesis
• Blood islands
• Chick embryos
• Vasculogenesis

• Animals
• Antigens, CD/genetics
• Cadherins/genetics
• Chick Embryo
• Chorioallantoic Membrane/blood supply
• Chorioallantoic Membrane/drug effects
• Fibroblast Growth Factor 2/genetics
• Hexanones/toxicity
• Neovascularization, Physiologic/drug effects
• Neurotoxins/toxicity
• Protein-Tyrosine Kinases/genetics
• Reactive Oxygen Species/metabolism
• Ribonuclease, Pancreatic/genetics
• Vascular Endothelial Growth Factor Receptor-2/genetics
• Vascular Endothelial Growth Factor Receptor-3/genetics
• Yolk Sac/blood supply
• Yolk Sac/drug effects