- Folate manages cell shape during neurulation. [Journal Article]
- SciScience 2017 Apr 07; 356(6333):38-39
- Folate receptor 1 is necessary for neural plate cell apical constriction during Xenopus neural tube formation. [Journal Article]
- DDevelopment 2017 Apr 15; 144(8):1518-1530
- Folate supplementation prevents up to 70% of neural tube defects (NTDs), which result from a failure of neural tube closure during embryogenesis. The elucidation of the mechanisms underlying folate a...
Folate supplementation prevents up to 70% of neural tube defects (NTDs), which result from a failure of neural tube closure during embryogenesis. The elucidation of the mechanisms underlying folate action has been challenging. This study introduces Xenopus laevis as a model to determine the cellular and molecular mechanisms involved in folate action during neural tube formation. We show that knockdown of folate receptor 1 (Folr1; also known as FRα) impairs neural tube formation and leads to NTDs. Folr1 knockdown in neural plate cells only is necessary and sufficient to induce NTDs. Folr1-deficient neural plate cells fail to constrict, resulting in widening of the neural plate midline and defective neural tube closure. Pharmacological inhibition of folate action by methotrexate during neurulation induces NTDs by inhibiting folate interaction with its uptake systems. Our findings support a model in which the folate receptor interacts with cell adhesion molecules, thus regulating the apical cell membrane remodeling and cytoskeletal dynamics necessary for neural plate folding. Further studies in this organism could unveil novel cellular and molecular events mediated by folate and lead to new ways of preventing NTDs.
- Junctional neural tube defect in a newborn: report of a fourth case. [Journal Article]
- CNChilds Nerv Syst 2017 Feb 28
- CONCLUSIONS: Characterized by an error in junctional neurulation in which the primary and secondary NT fail to integrate appropriately, JNTD has been recently classified. We believe the current patient to represent only the fourth reported case of JNTD in the literature.
- Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study. [Journal Article]
- PNPLoS Negl Trop Dis 2017; 11(2):e0005363
- The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infect...
The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5-9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes.
- Neural tube closure: cellular, molecular and biomechanical mechanisms. [Review]
- DDevelopment 2017 Feb 15; 144(4):552-566
- Neural tube closure has been studied for many decades, across a range of vertebrates, as a paradigm of embryonic morphogenesis. Neurulation is of particular interest in view of the severe congenital ...
Neural tube closure has been studied for many decades, across a range of vertebrates, as a paradigm of embryonic morphogenesis. Neurulation is of particular interest in view of the severe congenital malformations - 'neural tube defects' - that result when closure fails. The process of neural tube closure is complex and involves cellular events such as convergent extension, apical constriction and interkinetic nuclear migration, as well as precise molecular control via the non-canonical Wnt/planar cell polarity pathway, Shh/BMP signalling, and the transcription factors Grhl2/3, Pax3, Cdx2 and Zic2. More recently, biomechanical inputs into neural tube morphogenesis have also been identified. Here, we review these cellular, molecular and biomechanical mechanisms involved in neural tube closure, based on studies of various vertebrate species, focusing on the most recent advances in the field.
- Covalent growth factor tethering to direct neural stem cell differentiation and self-organization. [Journal Article]
- ABActa Biomater 2017 Feb 02
- Tethered growth factors offer exciting new possibilities for guiding stem cell behavior. However, many of the current methods present substantial drawbacks which can limit their application and confo...
Tethered growth factors offer exciting new possibilities for guiding stem cell behavior. However, many of the current methods present substantial drawbacks which can limit their application and confound results. In this work, we developed a new method for the site-specific covalent immobilization of azide-tagged growth factors and investigated its utility in a model system for guiding neural stem cell (NSC) behavior. An engineered interferon-γ (IFN-γ) fusion protein was tagged with an N-terminal azide group, and immobilized to two different dibenzocyclooctyne-functionalized biomimetic polysaccharides (chitosan and hyaluronan). We successfully immobilized azide-tagged IFN-γ under a wide variety of reaction conditions, both in solution and to bulk hydrogels. To understand the interplay between surface chemistry and protein immobilization, we cultured primary rat NSCs on both materials and showed pronounced biological effects. Expectedly, immobilized IFN-γ increased neuronal differentiation on both materials. Expression of other lineage markers varied depending on the material, suggesting that the interplay of surface chemistry and protein immobilization plays a large role in nuanced cell behavior. We also investigated the bioactivity of immobilized IFN-γ in a 3D environment in vivo and found that it sparked the robust formation of neural tube-like structures from encapsulated NSCs. These findings support a wide range of potential uses for this approach and provide further evidence that adult NSCs are capable of self-organization when exposed to the proper microenvironment.
- New classification of spinal lipomas based on embryonic stage. [Journal Article]
- JNJ Neurosurg Pediatr 2017; 19(4):428-439
- CONCLUSIONS: Secondary neurulation of the spinal cord gives rise to the conus medullaris and filum terminale, which are often involved in spinal lipomas. Formation of spinal lipomas seems to be a continuous process overlapping primary and secondary neurulation in some cases. Association with other anomalies was higher in Type 2-4 spinal lipomas, which included failed secondary neurulation, than in Type 1 lipomas, with failed primary neurulation. On the other hand, radical resection was indicated for Type 1, but not for Type 2, spinal lipomas. The new classification of spinal lipomas based on embryonic stage has the potential for clinical use and agrees well with both clinical and surgical findings. The classification proposed here is still preliminary. Further studies and verification are necessary to establish its clinical utility.
- Myelomeningocele Repair: Surgical Management Based on a 30-Year Experience. [Journal Article]
- ANActa Neurochir Suppl 2017; 124:143-148
- CONCLUSIONS: Accuracy and attention to the reconstruction are crucial for achieving good results and avoiding perioperative complications.
- A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family. [Journal Article]
- HMHum Mol Genet 2017 Mar 15; 26(6):1104-1114
- Anencephaly (APH) is characterized by the absence of brain tissues and cranium. During primary neurulation stage of the embryo, the rostral part of the neural pore fails to close, leading to APH. APH...
Anencephaly (APH) is characterized by the absence of brain tissues and cranium. During primary neurulation stage of the embryo, the rostral part of the neural pore fails to close, leading to APH. APH shows a heterogeneous etiology, ranging from environmental to genetic causes. The autosomal recessive inheritance of APH has been reported in several populations. In this study, we employed whole-exome sequencing and identified a homozygous missense mutation c.1522C > A (p.Pro508Thr) in the TRIM36 gene as the cause of autosomal recessive APH in an Indian family. The TRIM36 gene is expressed in the developing brain, suggesting a role in neurogenesis. In silico analysis showed that proline at codon position 508 is highly conserved in 26 vertebrate species, and the mutation is predicted to affect the conformation of the B30.2/SPRY domain of TRIM36. Both in vitro and in vivo results showed that the mutation renders the TRIM36 protein less stable. TRIM36 is known to associate with microtubules. Transient expression of the mutant TRIM36 in HeLa and LN229 cells resulted in microtubule disruption, disorganized spindles, loosely arranged chromosomes, multiple spindles, abnormal cytokinesis, reduced cell proliferation and increased apoptosis as compared with cells transfected with its wild-type counterpart. The siRNA knock down of TRIM36 in HeLa and LN229 cells also led to reduced cell proliferation and increased apoptosis. We suggest that microtubule disruption and disorganized spindles mediated by mutant TRIM36 affect neural cell proliferation during neural tube formation, leading to APH.
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- A Submerged Filter Paper Sandwich for Long-term Ex Ovo Time-lapse Imaging of Early Chick Embryos. [Journal Article]
- JVJ Vis Exp 2016 Dec 28; (118)
- Due to its availability, low cost, flat geometry, and transparency, the ex ovo chick embryo has become a major vertebrate animal model for the study of morphogenetic events, such as gastrulation(2), ...
Due to its availability, low cost, flat geometry, and transparency, the ex ovo chick embryo has become a major vertebrate animal model for the study of morphogenetic events, such as gastrulation(2), neurulation(3)(-)(5), somitogenesis(6), heart bending(7,8), and brain formation(9)(-)(13), during early embryogenesis. Key to understanding morphogenetic processes is to follow them dynamically by time-lapse imaging. The acquisition of time-lapse movies of chick embryogenesis ex ovo has been limited either to short time windows or to the need for an incubator to control temperature and humidity around the embryo(14). Here, we present a new technique to culture chick embryos ex ovo for high-resolution time-lapse imaging using transmitted light microscopy. The submerged filter paper sandwich is a variant of the well-established filter paper carrier technique (EC-culture)(1) and allows for the culturing of chick embryos without the need for a climate chamber. The embryo is sandwiched between two identical filter paper carriers and is kept fully submerged in a simple, temperature-controlled medium covered by a layer of light mineral oil. Starting from the primitive streak stage (Hamburger-Hamilton stage 5, HH5)(15) up to at least the 28-somite stage (HH16)(15), embryos can be cultured with either their ventral or dorsal side up. This allows the acquisition of time-lapse movies covering about 30 hr of embryonic development. Representative time-lapse frames and movies are shown. Embryos are compared morphologically to an embryo cultured in the standard EC-culture. The submerged filter paper sandwich provides a stable environment to study early dorsal and ventral morphogenetic processes. It also allows for live fluorescence imaging and micromanipulations, such as microsurgery, bead implantation, microinjection, gene silencing, and electroporation, and has a strong potential to be combined with immersion objectives for laser-based imaging (including light-sheet microscopy).