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- Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway. [JOURNAL ARTICLE]
- Hum Mol Genet 2013 Nov 18.
Wnt signaling has been classified as canonical Wnt/β-catenin-dependent or non-canonical planar cell polarity (PCP) pathway. Misregulation of either pathway is linked mainly to cancer or neural tube defects (NTDs), respectively. Both pathways seem to antagonize each other, and recent studies have implicated a number of molecular switches that activate one pathway while simultaneously inhibiting the other thereby partially mediating this antagonism. The lipoprotein receptor-related protein Lrp6 is crucial for the activation of the Wnt/β-catenin pathway, but its function in Wnt/PCP signaling remains largely unknown. In this study, we investigate the role of Lrp6 as a molecular switch between both Wnt pathways in a novel ENU mouse mutant of Lrp6 (Skax26(m1Jus)) and in human NTDs. We demonstrate that Skax26(m1Jus) represents a hypermorphic allele of Lrp6 with increased Wnt canonical and abolished PCP-induced JNK activities. We also show that Lrp6(Skax26-Jus) genetically interacts with a PCP mutant (Vangl2(Lp)) where double heterozygotes showed an increased frequency of NTDs and defects in cochlear hair cells' polarity. Importantly, our study also demonstrates the association of rare and novel missense mutations in LRP6 that is an inhibitor rather than an activator of the PCP pathway with human NTDs. We show that three LRP6 mutations in NTDs led to a reduced Wnt canonical activity and enhanced PCP signaling. Our data confirm an inhibitory role of Lrp6 in PCP signaling in neurulation and indicate the importance of a tightly regulated and highly dosage-sensitive antagonism between both Wnt pathways in this process.
- Hemichordate neurulation and the origin of the neural tube. [Journal Article]
- Nat Commun 2013 Nov 1.:2713.
The origin of the body plan of our own phylum, Chordata, is one of the most fascinating questions in evolutionary biology. Yet, after more than a century of debate, the evolutionary origins of the neural tube and notochord remain unclear. Here we examine the development of the collar nerve cord in the hemichordate Balanoglossus simodensis and find shared gene expression patterns between hemichordate and chordate neurulation. Moreover, we show that the dorsal endoderm of the buccal tube and the stomochord expresses Hedgehog RNA, and it seems likely that collar cord cells can receive the signal. Our data suggest that the endoderm functions as an organizer to pattern the overlying collar cord, similar to the relationship between the notochord and neural tube in chordates. We propose that the origin of the core genetic mechanisms for the development of the notochord and the neural tube date back to the last common deuterostome ancestor.
- IFT88 plays a cilia- and PCP-independent role in controlling oriented cell divisions during vertebrate embryonic development. [Journal Article, Research Support, Non-U.S. Gov't]
- Cell Rep 2013 Oct 17; 5(1):37-43.
The role for cilia in establishing planar cell polarity (PCP) is contentious. Although knockdown of genes known to function in ciliogenesis has been reported to cause PCP-related morphogenesis defects in zebrafish, genetic mutations affecting intraflagellar transport (IFT) do not show PCP phenotypes despite the requirement for IFT in cilia formation. This discrepancy has been attributed to off-target effects of antisense morpholino oligonucleotide (MO) injection, confounding maternal effects in zygotic mutant embryos, or an inability to distinguish between cilia-dependent versus cilia-independent protein functions. To determine the role of cilia in PCP, we generated maternal + zygotic IFT88 (MZift88) mutant zebrafish embryos, which never form cilia. We clearly demonstrate that cilia are not required to establish PCP. Rather, IFT88 plays a cilia-independent role in controlling oriented cell divisions at gastrulation and neurulation. Our results have important implications for the interpretation of cilia gene function in normal development and in disease.
- A BMP regulatory network controls ectodermal cell fate decisions at the neural plate border. [Journal Article, Research Support, Non-U.S. Gov't]
- Development 2013 Nov; 140(21):4435-44.
During ectodermal patterning the neural crest and preplacodal ectoderm are specified in adjacent domains at the neural plate border. BMP signalling is required for specification of both tissues, but how it is spatially and temporally regulated to achieve this is not understood. Here, using a transgenic zebrafish BMP reporter line in conjunction with double-fluorescent in situ hybridisation, we show that, at the beginning of neurulation, the ventral-to-dorsal gradient of BMP activity evolves into two distinct domains at the neural plate border: one coinciding with the neural crest and the other abutting the epidermis. In between is a region devoid of BMP activity, which is specified as the preplacodal ectoderm. We identify the ligands required for these domains of BMP activity. We show that the BMP-interacting protein Crossveinless 2 is expressed in the BMP activity domains and is under the control of BMP signalling. We establish that Crossveinless 2 functions at this time in a positive-feedback loop to locally enhance BMP activity, and show that it is required for neural crest fate. We further demonstrate that the Distal-less transcription factors Dlx3b and Dlx4b, which are expressed in the preplacodal ectoderm, are required for the expression of a cell-autonomous BMP inhibitor, Bambi-b, which can explain the specific absence of BMP activity in the preplacodal ectoderm. Taken together, our data define a BMP regulatory network that controls cell fate decisions at the neural plate border.
- Neural tube defects, folate, and immune modulation. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Birth Defects Res A Clin Mol Teratol 2013 Sep; 97(9):602-9.
Periconceptional supplementation with folic acid has led to a significant worldwide reduction in the incidence of neural tube defects (NTDs). However, despite increasing awareness of the benefits of folic acid supplementation and the implementation of food fortification programs in many countries, NTDs continue to be a leading cause of perinatal morbidity and mortality worldwide. Furthermore, there exists a significant subgroup of women who appear to be resistant to the protective effects of folic acid supplementation. The following review addresses emerging clinical and experimental evidence for a role of the immune system in the etiopathogenesis of NTDs, with the aim of developing novel preventative strategies to further reduce the incidence of NTD-affected pregnancies. In particular, recent studies demonstrating novel roles and interactions between innate immune factors such as the complement cascade, neurulation, and folate metabolism are explored.
- Spatial-temporal expressions of Crumbs and Nagie oko and their interdependence in zebrafish central nervous system during early development. [Journal Article]
- Int J Dev Neurosci 2013 Dec; 31(8):770-82.
A vast number of apicobasal polarity proteins play essential roles in the polarization and morphogenesis of the neuroepithelia. Crumbs (Crb) type I transmembrane cell-cell adhesion proteins are among these proteins. Five crb genes have been identified in zebrafish. However, their expressional and functional differences during early neural development remain to be fully elucidated. Here, we study the spatial-temporal expression patterns and functions of Crb1, Crb2a, and Crb2b in the central nervous system (CNS) during the neurulation period. We show that: 1, the optic vesicle and undifferentiated retinal neuroepithelium only express Crb2a; 2, Crb1 and Crb2a expressions overlap extensively in the undifferentiated neural tube epithelium; 3, Crb2b expression is the weakest of the three and is restricted to the ventral-most regions of the anterior CNS; and 4, Nok and Crb proteins require each other for their apical localization in neuroepithelium. The commencements of Crb1, Crb2a, and Crb2b expressions follow a spatial-temporal spread from anterior to posterior and from ventral to dorsal and lag behind that of adherens junction components, such as ZO-1 and actin bundles. Genetic and morpholino suppression analyses suggest that in regions where these Crb expressions overlap, they are functionally redundant in maintaining apicobasal polarity of the undifferentiated neuroepithelium.
- Wnt11b Is Involved in Cilia-Mediated Symmetry Breakage during Xenopus Left-Right Development. [Journal Article]
- PLoS One 2013; 8(9):e73646.
Breakage of bilateral symmetry in amphibian embryos depends on the development of a ciliated epithelium at the gastrocoel roof during early neurulation. Motile cilia at the gastrocoel roof plate (GRP) give rise to leftward flow of extracellular fluids. Flow is required for asymmetric gene expression and organ morphogenesis. Wnt signaling has previously been involved in two steps, Wnt/ß-catenin mediated induction of Foxj1, a regulator of motile cilia, and Wnt/planar cell polarity (PCP) dependent cilia polarization to the posterior pole of cells. We have studied Wnt11b in the context of laterality determination, as this ligand was reported to activate canonical and non-canonical Wnt signaling. Wnt11b was found to be expressed in the so-called superficial mesoderm (SM), from which the GRP derives. Surprisingly, Foxj1 was only marginally affected in loss-of-function experiments, indicating that another ligand acts in this early step of laterality specification. Wnt11b was required, however, for polarization of GRP cilia and GRP morphogenesis, in line with the known function of Wnt/PCP in cilia-driven leftward flow. In addition Xnr1 and Coco expression in the lateral-most GRP cells, which sense flow and generate the first asymmetric signal, was attenuated in morphants, involving Wnt signaling in yet another process related to symmetry breakage in Xenopus.
- Fibroblast Growth Factor-2 Signaling in Neurogenesis and Neurodegeneration. [JOURNAL ARTICLE]
- J Neuroimmune Pharmacol 2013 Sep 21.
Fibroblast growth factor-2 (FGF2), also known as basic FGF, is a multi-functional growth factor. One of the 22-member FGF family, it signals through receptor tyrosine kinases encoding FGFR1-4. FGF2 activates FGFRs in cooperation with heparin or heparin sulfate proteoglycan to induce its pleiotropic effects in different tissues and organs, which include potent angiogenic effects and important roles in the differentiation and function of the central nervous system (CNS). FGF2 is crucial to development of the CNS, which explains its importance in adult neurogenesis. During development, high levels of FGF2 are detected from neurulation onwards. Moreover, developmental expression of FGF2 and its receptors is temporally and spatially regulated, concurring with development of specific brain regions including the hippocampus and substantia nigra pars compacta. In adult neurogenesis, FGF2 has been implicated based on its expression and regulation of neural stem and progenitor cells in the neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. FGFR1 signaling also modulates inflammatory signaling through the surface glycoprotein CD200, which regulates microglial activation. Because of its importance in adult neurogenesis and neuroinflammation, manipulation of FGF2/FGFR1 signaling has been a focus of therapeutic development for neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and traumatic brain injury. Novel strategies include intranasal administration of FGF2, administration of an NCAM-derived FGFR1 agonist, and chitosan-based nanoparticles for the delivery of FGF2 in pre-clinical animal models. In this review, we highlight current research towards therapeutic interventions targeting FGF2/FGFR1 in neurodegenerative disorders.
- Transcriptional and Epigenetic Regulation of Neural Crest Induction during Neurulation. [Journal Article]
- Dev Neurosci 2013; 35(5):361-72.
Neurulation is one of the many important events in mammalian development. It is the stage of organogenesis in vertebrate embryos during which the neural tube is transformed into the primitive structures that will later develop into the central nervous system. Recent transcriptome analysis during neurulation and early organogenesis in humans and mice has identified the global dynamics of gene expression changes across developmental time. This has revealed a richer understanding of gene regulation and provides hints at the transcriptional regulatory networks that underlie these processes. Similarly, epigenome analysis, which collectively constitutes histone modifications, transcription factor binding, and other structural features associated with gene regulation, has given a renewed appreciation to the subtle mechanisms involving the process of neurulation. More specifically, the histone demethylases KDM4A and KDM6B have recently been shown to be key histone H3K4 and H3K27 modifiers that regulate neural crest specification and neural tube closure. Additionally, miRNAs have recently been shown to influence transcription of genes directly or by altering the levels of epigenetic modifiers and thus regulate gene expression. This mini review briefly summarizes the literature, highlighting the transcriptional and epigenetic regulation of key genes involved in neural crest induction and neural crest specification by transcription factors and miRNAs. Understanding how these mechanisms work individually and in clusters will shed light on pathways in the context of diseases associated with neural crest cell derivatives such as melanoma, cardiovascular defects and neuronal craniofacial defects. © 2013 S. Karger AG, Basel.
- Complex forms of spinal dysraphism. [Journal Article]
- Childs Nerv Syst 2013 Sep; 29(9):1527-32.
Spinal dysraphisms are a heterogeneous group of congenital malformations involving the bony component of vertebrae or spinal cord or both. Simple forms include the contiguous, solitary malformations such as myelomeningocele and diastematomyelia, and can be either aperta or occulta type.Complex forms include various types of spinal malformations occurring in combination, one type of malformations occurring at multiple levels in noncontiguous manner or spinal dysraphisms with other organ anomalies. Anomalous development in gastrulation, primary neurulation, and secondary neurulation stage in variable proportions give rise to these types of complex malformations. These cases can be diagnosed postnatally in early infancy by the strong clinical suspicion, supplemented by whole spinal axis and cranial magnetic resonance imaging (MRI) screening, to detect any occult spinal dysraphisms like split cord malformations, neurenteric cyst, lipoma, or cranial anomalies like Chiari malformations and hydrocephalus. Computed tomography and MRI are the gold standard to detect bony anomalies and cord malformations, respectively. Complex spinal dysraphisms, to our mind, should always be tried to be corrected in single operative stage, however, in case of ruptured defects, correction through multiple operations can be considered.Overall, prognosis of complex forms of spinal dysraphism is poor in comparison to their simple forms and depends on preoperative neurological status and the nature of complex dyraphism. We discuss the classification, embryogenesis, investigation, and treatment protocol with review of literature of such complex anomalies.