DOCSLIB.ORG

Deficits in Early Neural Tube Identity Found in CHARGE Syndrome

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Deficits in Early Neural Tube Identity Found in CHARGE Syndrome INSIGHT elife.elifesciences.org CEREBELLAR MALFORMATION Deficits in early neural tube identity found in CHARGE syndrome Long predicted from studies of model vertebrates, the first human example of abnormal patterning of the early neural tube leading to underdevelopment of the cerebellum has been demonstrated. PARTHIV HALDIPUR AND KATHLEEN J MILLEN work by Yu et al. shows that loss of CHD7 also Related research article Yu T, Meiners LC, disrupts the development of the early neural tube, Danielsen K, Wong MTY, Bowler T, which is the forerunner of the central nervous sys- Reinberg D, Scambler PJ, van Ravenswaaij- tem. This results in underdevelopment (hypoplasia) of the cerebellar vermis. This finding is extremely Arts CMA, Basson MA. 2013. Deregulated exciting as it represents the very first example of FGF and homeotic gene expression this particular class of neural birth defect to be underlies cerebellar vermis hypoplasia in observed in humans. CHARGE syndrome. eLife 2:e01305. One of the first steps in the development of the central nervous system is the establishment of doi: 10.7554/eLife.01305 gene expression domains that segment the neural Image MRI scan of a patient with CHARGE tube into the regions that become the forebrain, syndrome the midbrain, the hindbrain and the spinal cord. Subsequently, signalling centres establish the boundaries between these regions and secrete HARGE syndrome is a genetic condition growth factors which pattern the adjacent nervous that involves multiple malformations in tissue (Kiecker and Lumsden, 2012). The best Cnewly born children. The acronym stands understood signalling centre is the Isthmic for coloboma (a hole in the eye), heart defects, Organizer, which forms at the boundary of the choanal atresia (a blockage of the nasal pas- midbrain and the hindbrain. This centre secretes sage), retarded growth and development, gen- fibroblast growth factor 8 (Fgf8) and other growth ital abnormalities, and ear anomalies (Lalani et al., factors, and is essential for defining the regions of 2012). Now, in eLife, Albert Basson of King’s the neural plate that will become the posterior College London (KCL) and co-workers—including midbrain and the cerebellum (Figure 1). Tim Yu of KCL as first author—report that under- Extensive experiments in model vertebrates development of a region of the cerebellum called (such as mice, chickens and zebrafish) have shown Copyright Haldipur and Millen. the vermis is also associated with CHARGE syn- that if the Isthmic Organizer fails to develop, This article is distributed under the drome (Yu et al., 2013). there is dramatic and rapid cell death in adjacent terms of the Creative Commons Most cases of CHARGE syndrome can be regions of the neural tube. Mutant mice in which Attribution License, which permits related to a mutation in the gene that encodes the Isthmic Organizer cannot express Fgf8 at all unrestricted use and redistribution provided that the original author and CHD7, a protein that is involved in remodelling do not survive post-natally (Chi et al., 2003). source are credited. chromatin (Janssen et al., 2012). The latest However, reduced Fgf8 signalling or a failure to Haldipur and Millen. eLife 2013;2:e01873. DOI: 10.7554/eLife.01873 1 of 3 Insight Cerebellar malformation | Deficits in early neural tube identity found in CHARGE syndrome MB Organizer disorders might not be compatible with HB survival in humans. CB Anterior MB Otx2 Previously several clinical reports had noted SC cerebellar deficits in a few CHARGE syndrome IsO Fgf8 patients. Now Yu, Basson and co-workers—who CB are based in London, Groningen and New Gbx2 Posterior Vermis York—report the results of MRI scans of a large cohort of 20 patients with CHARGE syndrome (caused by a mutation in CHD7; Yu et al., 2013). Figure 1. The role of the Isthmic Organizer. The They confirm multiple cerebellar abnormalities establishment of gene expression domains along the in 55% of these patients, with 25% of the patients anterior-posterior axis helps to segment the develop- having cerebellar vermis hypoplasia. ing brain into the forebrain, midbrain (MB), hindbrain Yu et al. also report the results of experiments (HB) and spinal cord (SC). Signalling centres estab- of mice lacking one or both working copies of the lished at the boundaries between these segments Chd7 gene. Mice lacking one working copy of the secrete growth factors which pattern the adjacent nervous tissue. The Isthmic Organizer (IsO; shown in gene did not have any obvious cerebellar pheno- yellow) forms at the boundary of the posterior type, but cerebellar vermis hypoplasia was evi- midbrain and anterior hindbrain: the IsO secretes dent when one copy of the Fgf8 gene was also Fgf8 and other growth factors, and is essential for removed, suggesting genetic synergy between defining the regions of the neural plate that will Chd7 and Fgf8. Expression of Fgf8 and its down- become the posterior midbrain (shown in blue) and stream gene Etv5 were significantly down regulated the cerebellum (CB; green). The homeobox genes at the junction of the midbrain and the hindbrain Otx2 and Gbx2 are involved in the formation of the during the early development of Chd7 mutant IsO and in regulating the expression of Fgf8 by the mice. Thus, reduced Fgf8 expression represents an IsO. Mutations in the CHARGE syndrome gene, underlying cause of CHARGE-related vermis hypo- CHD7, can alter Otx2, Gbx2 and Fgf8 expression, plasia because cerebellar development is exquis- resulting in underdevelopment of a region of the cerebellum called the vermis (right). itely sensitive to the level of Fgf8 signalling. Going one step further, Yu et al. next demon- strated that the expression of two genes that reg- maintain Fgf8 expression does not result in animal ulate Fgf8 expression at the Isthmic Organizer death, but rather causes cerebellar vermis hypo- (Otx2 and Gbx2) is altered in mice lacking both plasia (Basson et al., 2008; Sato and Joyner, working copies of the Chd7 gene. Chromatin immu- 2009). The genetic regulatory network that leads noprecipitation assays subsequently revealed that to the formation of the Isthmic Organizer is Chd7 is associated with enhancer elements belong- highly conserved across vertebrates, and beyond ing to the Otx2 and Gbx2 genes, which suggests (Robertshaw and Kiecker, 2012), and it has long that Chd7 has a direct role in regulating these been postulated that disruption of the Isthmic essential Isthmic Organizer genes. Organizer must, therefore, be a cause of human Together these results provide substantial cerebellar malformation. However, until now, evidence that cerebellar vermis hypoplasia in this classical developmental phenotype had not CHARGE syndrome is caused by dysfunction been recognized in human patients. of the Isthmic Organizer in the early embryo. With recent developments in neuroimaging, Further, the work of Basson, Yu and co-workers neuropathology and neurogenetics, many devel- suggests that Isthmic Organizer disruption may opmental disorders of the cerebellum, including be a more common cause of human cerebellar cerebellar vermis hypoplasia, have emerged malformation than previously thought. Although as causes of neurodevelopmental dysfunction complete loss-of-function mutations in genes (Doherty et al., 2013). Together, these disor- that are central to the formation of the Isthmic ders are relatively common, occurring roughly Organizer (such as Otx2, Gbx2 and Fgf8) are still once in every 3000 live births. Cerebellar mal- likely to be incompatible with human life, this formations can occur in isolation or as part of study implies that genes which regulate the ex- a broader malformation syndrome involving mul- pression of central Isthmic Organizer genes may tiple systems. Although several cerebellar malfor- cause cerebellar malformation when mutated. mation genes have been identified, no gene directly CHD7 is expressed in a wide variety of tissues involved in the formation or function of the Isthmic during development, and CHARGE syndrome Organizer had previously been implicated in phenotypes indicate that it has tissue-specific FIGURE MODIFIED FROM BASSON AND WINGATE, 2013 this class of birth defect, suggesting that Isthmic and developmental stage-specific roles. A difficult Haldipur and Millen. eLife 2013;2:e01873. DOI: 10.7554/eLife.01873 2 of 3 Insight Cerebellar malformation | Deficits in early neural tube identity found in CHARGE syndrome question remains as to how CHD7 achieves during development. Development 135:889–898. different functions in different tissues. For example doi: 10.1242/dev.011569. although loss of Chd7 disrupts Isthmic Organizer Basson A, Wingate R. 2013. Congenital hypoplasia of the cerebellum: developmental causes and behavioural Fgf8 expression, Fgf8 expression is normal in the consequences. Frontiers in Neuroanatomy 7:29. adjacent pharyngeal arches of the embryo. One doi: 10.3389/fnana.2013.00029. possibility is that Cdh7 has different binding Chi CL, Martinez S, Wurst W, Martin GR. 2003. The partners in different tissues. isthmic organizer signal FGF8 is required for cell Intriguingly, it has recently been shown that survival in the prospective midbrain and cerebellum, in the prospective midbrain and cerebellum. Cdh7 interacts with a small number of other Development 130:2633–2644. doi: 10.1242/ transcription factors in neural stem cells, and that dev.00487. mutations in these other factors underlie a number Doherty D, Millen KJ, Barkovich AJ. 2013. Midbrain of human malformation disorders (Engelen et al., and hindbrain malformations: advances in clinical Lancet Neurology 2011). One exciting prediction of this finding in diagnosis, imaging, and genetics. 12:381–393. doi: 10.1016/S1474-4422(13)70024-3. combination with the work of Yu et al. on CHD7, Engelen E, Akinci U, Bryne JC, Hou J, Gontan C, is that systematic analysis of cerebellar mor- Moen M, Szumska D, Kockx C, van Ijcken W, phology may uncover previously unrecognized Dekkers DH, et al. 2011. Sox2 cooperates with Chd7 cerebellar deficits related to Isthmic Organizer to regulate genes that are mutated in human syndromes.
Load more

Recommended publications
  • Wnt Signal Specifies the Intrathalamic Limit and Its Organizer Properties by Regulating Shh Induction in the Alar Plate
    The Journal of Neuroscience, February 27, 2013 • 33(9):3967–3980 • 3967 Development/Plasticity/Repair Wnt Signal Specifies the Intrathalamic Limit and Its Organizer Properties by Regulating Shh Induction in the Alar Plate Almudena Martinez-Ferre,* Maria Navarro-Garberi,* Carlos Bueno, and Salvador Martinez Institute of Neurosciences, Miguel Herna´ndez University–Spanish National Research Council, 03550 San Juan, Alicante, Spain The structural complexity of the brain depends on precise molecular and cellular regulatory mechanisms orchestrated by regional morphogenetic organizers. The thalamic organizer is the zona limitans intrathalamica (ZLI), a transverse linear neuroepithelial domain in the alar plate of the diencephalon. Because of its production of Sonic hedgehog, ZLI acts as a morphogenetic signaling center. Shh is expressed early on in the prosencephalic basal plate and is then gradually activated dorsally within the ZLI. The anteroposterior posi- tioning and the mechanism inducing Shh expression in ZLI cells are still partly unknown, being a subject of controversial interpretations. For instance, separate experimental results have suggested that juxtaposition of prechordal (rostral) and epichordal (caudal) neuroep- ithelium, anteroposterior encroachment of alar lunatic fringe (L-fng) expression, and/or basal Shh signaling is required for ZLI specifi- cation. Here we investigated a key role of Wnt signaling in the molecular regulation of ZLI positioning and Shh expression, using experimental embryology in ovo in the chick. Early Wnt expression in the ZLI regulates Gli3 and L-fng to generate a permissive territory in which Shh is progressively induced by planar signals of the basal plate. Introduction Vieira et al., 2005; Guinazu et al., 2007). However, Six3 is not The zona limitans intrathalamica (ZLI) is a neuroepithelial do- required for the formation of the mammalian ZLI (Lavado et al., main intercalated between the prethalamus and the thalamus in 2008).
    [Show full text]
  • EZH2 Is Essential for Fate Determination in the Mammalian Isthmic Area
    bioRxiv preprint doi: https://doi.org/10.1101/442111; this version posted October 12, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. EZH2 is essential for fate determination in the mammalian Isthmic area Iris Wever1, Cindy M.R.J. Wagemans1 and Marten P. Smidt1 1Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands bioRxiv preprint doi: https://doi.org/10.1101/442111; this version posted October 12, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The polycomb group proteins (PcGs) are a group of epigenetic factors associated with gene silencing. They are found in several families of multiprotein complexes, including Polycomb Repressive Complex (PRC) 2. EZH2, EED and SUZ12 form the core components of the PRC2 complex, which is responsible for the mono, di- and trimethylation of lysine 27 of histone 3 (H3K27Me3), the chromatin mark associated with gene silencing. Loss-of-function studies of Ezh2, the catalytic subunit of PRC2, have shown that PRC2 plays a role in regulating developmental transitions of neuronal progenitor cells; from self-renewal to differentiation and the neurogenic-to-gliogenic fate switch. To further address the function of EZH2 and H3K27me3 during neuronal development we generated a conditional mutant in which Ezh2 was removed in the mammalian isthmic (mid-hindbrain) region from E10.5 onward. Loss of Ezh2 changed the molecular coding of the anterior ventral hindbrain leading to a fate switch and the appearance of ectopic dopaminergic neurons.
    [Show full text]
  • Experimental Study of MAP Kinase Phosphatase-3 (Mkp3) Expression in the Chick Neural Tube in Relation to Fgf8 Activity
    Brain Research Reviews 49 (2005) 158–166 www.elsevier.com/locate/brainresrev Review Experimental study of MAP kinase phosphatase-3 (Mkp3) expression in the chick neural tube in relation to Fgf8 activity Claudia Vieira, Salvador MartinezT Neuroscience Institute UMH-CSIC, University Miguel Hernandez, N-332, Km 87, E-03550 San Juan de Alicante, Spain Accepted 8 December 2004 Available online 7 April 2005 Abstract Mitogen-activated protein kinase (MAPK) pathways are well known to be involved in signal transduction from extracellular to intracellular compartments in all eukaryotes. The activation of this cascade will have an effect on cell proliferation, differentiation, and apoptosis. In this study, we describe the cloning of the chick Mkp3 gene that is highly homologous to the mammalian gene and are both expressed in several embryo regions with demonstrated morphogenetic activity. In early developmental stages, Mkp3 and Fgf8 have similar expression patterns. Differences in the activation of Mkp3 transcription in the isthmus and the repression with FGF receptor inhibition suggest that Fgf8 protein controls Mkp3 transcription. Ectopically, expression of Fgf8 protein induces Mkp3 in a short period of time in the diencephalon, indicating a positive regulation of Mkp3 by Fgf8. Moreover, we show a distinct tissue competence to express Mkp3 rostrally and caudally to the zona limitans intrathalamica (ZLI). D 2005 Elsevier B.V. All rights reserved. Theme: Development and regeneration Topic: Pattern formation, compartments, and boundaries Keywords: Mid–hindbrain boundary; Isthmic organizer; Zona limitans intrathalamica; Mkp3; Fgf8; MAPK Contents 1. Introduction........................................................... 159 2. Materials and methods ..................................................... 159 2.1. Cloning of a chick homologue of Mkp3 .......................................
    [Show full text]
  • Her6 Regulates the Neurogenetic Gradient and Neuronal Identity in the Thalamus
    Her6 regulates the neurogenetic gradient and neuronal identity in the thalamus Steffen Scholppa,b,1, Alessio Delogua, Jonathan Gilthorpea,2, Daniela Peukerta,b, Simone Schindlerb, and Andrew Lumsdena aMRC Centre for Developmental Neurobiology, New Hunt’s House, Guy’s Campus, King’s College London, London SE1 1UL, United Kingdom; and bInstitute of Toxicology and Genetics, Institute of Technology Karlsruhe, Postfach 3640, 76021 Karlsruhe, Germany Communicated by Thomas M. Jessell, Columbia University College of Physicians and Surgeons, New York, NY, September 30, 2009 (received for review June 10, 2009) During vertebrate brain development, the onset of neuronal dif- expression of Ascl1 in the dorsal forebrain induces ectopic ferentiation is under strict temporal control. In the mammalian differentiation of GABAergic neurons (15). thalamus and other brain regions, neurogenesis is regulated also Another subfamily of bHLH proteins, the hairy-related Hes/ in a spatially progressive manner referred to as a neurogenetic Her proteins, generally function as DNA-binding transcriptional gradient, the underlying mechanism of which is unknown. Here we repressors and antagonize proneural gene function (16, 17). describe the existence of a neurogenetic gradient in the zebrafish Hairy-related proteins form homodimers through the bHLH thalamus and show that the progression of neurogenesis is con- region and have a conserved WRPW domain at the carboxyl (C) trolled by dynamic expression of the bHLH repressor her6. Mem- terminus, which functions as a repression domain by recruiting bers of the Hes/Her family are known to regulate proneural genes, co-repressors of the Groucho family (18). Some of these hairy- such as Neurogenin and Ascl.
    [Show full text]
  • The Role of Otx and Otp Genes in Brain Development
    Int. J. Dev. Biol. 44: 669-677 (2000) Otx and Otp genes in brain development 669 The role of Otx and Otp genes in brain development DARIO ACAMPORA, MARIA PIA POSTIGLIONE, VIRGINIA AVANTAGGIATO, MARIA DI BONITO and ANTONIO SIMEONE* International Institute of Genetics and Biophysics, Naples, Italy. ABSTRACT Over the last ten years, many genes involved in the induction, specification and regionalization of the brain have been identified and characterized at the functional level through a series of animal models. Among these genes, both Otx1 and Otx2, two murine homologues of the Drosophila orthodenticle (otd) gene which encode transcription factors, play a pivotal role in the morphogenesis of the rostral brain. Classical knock-out studies have revealed that Otx2 is fundamental for the early specification and subsequent maintenance of the anterior neural plate, whereas Otx1 is mainly necessary for both normal corticogenesis and sense organ development. A minimal threshold of both gene products is required for correct patterning of the fore-midbrain and positioning of the isthmic organizer. A third gene, Orthopedia (Otp) is a key element of the genetic pathway controlling development of the neuroendocrine hypothalamus. This review deals with a comprehensive analysis of the Otx1, Otx2 and Otp functions, and with the possible evolutionary implications suggested by the models in which the Otx genes are reciprocally replaced or substituted by the Drosophila homologue, otd. KEY WORDS: Brain patterning, brain evolution, visceral endoderm, neuroendocrine hypothalamus. Introduction romere (Cohen and Jürgens, 1990, 1991; Finkelstein and Perrimon, 1990; Finkelstein et al., 1990; Hirth et al., 1995; Younossi- Morphogenesis of the central nervous system (CNS) and differ- Hartenstein et al., 1997).
    [Show full text]
  • Conserved Genetic Patterning Mechanisms in Insect and Vertebrate Brain Development
    Heredity (2005) 94, 465–477 & 2005 Nature Publishing Group All rights reserved 0018-067X/05 $30.00 www.nature.com/hdy REVIEW Insights into the urbilaterian brain: conserved genetic patterning mechanisms in insect and vertebrate brain development R Lichtneckert and H Reichert Institute of Zoology, Biozentrum/Pharmazentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland Recent molecular genetic analyses of Drosophila melanogaster of the otd/Otx and ems/Emx gene families can functionally and mouse central nervous system (CNS) development replace each other in embryonic brain patterning. Homologous revealed strikingly similar genetic patterning mechanisms in genes involved in dorsoventral regionalization of the CNS in the formation of the insect and vertebrate brain. Thus, in both vertebrates and insects show remarkably similar patterning and insects and vertebrates, the correct regionalization and neuronal orientation with respect to the neurogenic region (ventral in identity of the anterior brain anlage is controlled by the cephalic insects and dorsal in vertebrates). This supports the notion gap genes otd/Otx and ems/Emx, whereas members of the that a dorsoventral body axis inversion occurred after the Hox genes are involved in patterning of the posterior brain. separation of protostome and deuterostome lineages in A third intermediate domain on the anteroposterior axis of the evolution. Taken together, these findings demonstrate con- vertebrate and insect brain is characterized by the expression of served genetic patterning mechanisms in insect and vertebrate the Pax2/5/8 orthologues, suggesting that the tripartite ground brain development and suggest a monophyletic origin of the plans of the protostome and deuterostome brains share a brain in protostome and deuterostome bilaterians.
    [Show full text]
  • EARLY ANTERIOR/POSTERIOR PATTERNING of the MIDBRAIN and CEREBELLUM Aimin Liu1 and Alexandra L Joyner1,2
    P1: GDL May 1, 2001 10:35 Annual Reviews AR121-28 Annu. Rev. Neurosci. 2001. 24:869–96 Copyright c 2001 by Annual Reviews. All rights reserved EARLY ANTERIOR/POSTERIOR PATTERNING OF THE MIDBRAIN AND CEREBELLUM Aimin Liu1 and Alexandra L Joyner1,2 Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, Departments of 1Cell Biology and 2Physiology & Neuroscience, New York University School of Medicine, New York, NY10016; e-mail: [email protected], [email protected] Key Words midbrain/hindbrain organizer, Fibroblast growth factor, Otx2, Gbx2, Engrailed ■ Abstract Transplantation studies performed in chicken embryos indicated that early anterior/posterior patterning of the vertebrate midbrain and cerebellum might be regulated by an organizing center at the junction between the midbrain and hindbrain. More than a decade of molecular and genetic studies have shown that such an organizer is indeed central to development of the midbrain and anterior hindbrain. Furthermore, a complicated molecular network that includes multiple positive and negative feedback loops underlies the establishment and refinement of a mid/hindbrain organizer, as well as the subsequent function of the organizer. In this review, we first introduce the expression patterns of the genes known to be involved in this patterning process and the quail-chick transplantation experiments that have provided the foundation for understanding the genetic pathways regulating mid/hindbrain patterning. Subsequently, we discuss the molecular genetic studies that have revealed the roles for many genes in normal early patterning of this region. Finally, some of the remaining questions and future directions are discussed.
    [Show full text]
  • Hes1 Regulates the Number and Anterior–Posterior Patterning of Mesencephalic Dopaminergic Neurons at the Mid/Hindbrain Boundary (Isthmus)
    Developmental Biology 358 (2011) 91–101 Contents lists available at ScienceDirect Developmental Biology journal homepage: www.elsevier.com/developmentalbiology Hes1 regulates the number and anterior–posterior patterning of mesencephalic dopaminergic neurons at the mid/hindbrain boundary (isthmus) Yoko Kameda a,⁎, Takayoshi Saitoh b, Takao Fujimura c a Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan b Graduate school of Science, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan c Department of Dermatology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan article info abstract Article history: The lack of the Hes1 gene leads to the failure of cranial neurulation due to the premature onset of neural Received for publication 12 January 2011 differentiation. Hes1 homozygous null mutant mice displayed a neural tube closure defect, and exencephaly Revised 22 June 2011 was induced at the mid/hindbrain boundary. In the mutant mesencephalon, the roof plate was not formed and Accepted 12 July 2011 therefore the ventricular zone showing cell proliferation was displaced to the brain surface. Furthermore, the Available online 23 July 2011 telencephalon and ventral diencephalon were defective. Despite the severe defects of neurogenesis in null mutants, the mesencephalic dopaminergic (mesDA) neurons were specified at the midline of the ventral Keywords: — fl Hes1 knockout mice mesencephalon in close proximity to two important signal centers oor plate and mid/hindbrain boundary Neural tube closure defect (i.e., the isthmic organizer). Using mesDA neuronal markers, tyrosine hydroxylase (TH) and Pitx3, the Mesencephalic dopaminergic neurons development of mesDA neurons was studied in Hes1 null mice and compared with that in the wild type.
    [Show full text]
  • Ancient Deuterostome Origins of Vertebrate Brain Signalling Centres
    ARTICLE doi:10.1038/nature10838 Ancient deuterostome origins of vertebrate brain signalling centres Ariel M. Pani1,2, Erin E. Mullarkey3*, Jochanan Aronowicz4*, Stavroula Assimacopoulos5, Elizabeth A. Grove3,4,5 & Christopher J. Lowe1,2,4 Neuroectodermal signalling centres induce and pattern many novel vertebrate brain structures but are absent, or divergent, in invertebrate chordates. This has led to the idea that signalling-centre genetic programs were first assembled in stem vertebrates and potentially drove morphological innovations of the brain. However, this scenario presumes that extant cephalochordates accurately represent ancestral chordate characters, which has not been tested using close chordate outgroups. Here we report that genetic programs homologous to three vertebrate signalling centres—the anterior neural ridge, zona limitans intrathalamica and isthmic organizer—are present in the hemichordate Saccoglossus kowalevskii. Fgf8/17/18 (a single gene homologous to vertebrate Fgf8, Fgf17 and Fgf18), sfrp1/5, hh and wnt1 are expressed in vertebrate-like arrangements in hemichordate ectoderm, and homologous genetic mechanisms regulate ectodermal patterning in both animals. We propose that these genetic programs were components of an unexpectedly complex, ancient genetic regulatory scaffold for deuterostome body patterning that degenerated in amphioxus and ascidians, but was retained to pattern divergent structures in hemichordates and vertebrates. During vertebrate development,the brainarises from coarsely patterned were secondarily simplified or lost along the lineages leading to the planar neuroectoderm through successive refinement of regional invertebrate chordates. identities,resulting after morphogenesis and growth ina complex struc- Hemichordates are a deuterostome phylum closely related to ture composed of highly specialized areas1–3. In contrast, invertebrate chordates26 and are a promising outgroup for investigating chordate chordates have relatively simple nervous systems that lack unambigu- evolution.
    [Show full text]
  • Generation of Isthmic Organizer-Like Cells from Human Embryonic Stem Cells
    Molecules and Cells Minireview Generation of Isthmic Organizer-Like Cells from Human Embryonic Stem Cells Junwon Lee1,2,3,5, Sang-Hwi Choi1,3,5, Dongjin R Lee1,3, Dae-Sung Kim4,*, and Dong-Wook Kim1,3,* 1Department of Physiology, 2Department of Ophthalmology, 3Brain Korea 21 PLUS Project for Medical Science, Yonsei Universi- ty College of Medicine, Seoul 03722, Korea, 4Department of Biotechnology, Brain Korea 21 PLUS Project for Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea, 5These authors contributed equally to this work. *Correspondence: [email protected] (DWK); [email protected] (DSK) http://dx.doi.org/10.14348/molcells.2018.2210 www.molcells.org The objective of this study was to induce the production of INTRODUCTION isthmic organizer (IsO)-like cells capable of secreting fibroblast growth factor (FGF) 8 and WNT1 from human embryonic The secondary organizer, a specific group of cells that stem cells (ESCs). The precise modulation of canonical Wnt emerges during early embryonic development, can influence signaling was achieved in the presence of the small molecule the identity of surrounding tissues (Kiecker and Lumsden, CHIR99021 (0.6 μM) during the neural induction of human 2012). These cells have the ability to secret morphogens, ESCs, resulting in the differentiation of these cells into IsO-like thus specifying the fate of adjacent cells in a space- and cells having a midbrain-hindbrain border (MHB) fate in a time-dependent manner, and elaborating the development manner that recapitulated their developmental course in vivo. of a given tissue. The isthmic organizer (IsO) in the verte- Resultant cells showed upregulated expression levels of FGF8 brate central nervous system (CNS) has been comprehen- and WNT1.
    [Show full text]
  • Journal.Pone.0039977
    Fgf8-Related Secondary Organizers Exert Different Polarizing Planar Instructions along the Mouse Anterior Neural Tube Ivan Crespo-Enriquez1, Juha Partanen2, Salvador Martinez1, Diego Echevarria1* 1 Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Cientı´ficas–Universidad Miguel Hernandez, Alicante, Spain, 2 Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland Abstract Early brain patterning depends on proper arrangement of positional information. This information is given by gradients of secreted signaling molecules (morphogens) detected by individual cells within the responding tissue, leading to specific fate decisions. Here we report that the morphogen FGF8 exerts initially a differential signal activity along the E9.5 mouse neural tube. We demonstrate that this polarizing activity codes by RAS-regulated ERK1/2 signaling and depends on the topographical location of the secondary organizers: the isthmic organizer (IsO) and the anterior neural ridge (anr) but not on zona limitans intrathalamica (zli). Our results suggest that Sprouty2, a negative modulator of RAS/ERK pathway, is important for regulating Fgf8 morphogenetic signal activity by controlling Fgf8-induced signaling pathways and positional information during early brain development. Citation: Crespo-Enriquez I, Partanen J, Martinez S, Echevarria D (2012) Fgf8-Related Secondary Organizers Exert Different Polarizing Planar Instructions along the Mouse Anterior Neural Tube. PLoS ONE 7(7): e39977. doi:10.1371/journal.pone.0039977 Editor: Alain Che´dotal, Institut de la Vision, France Received January 12, 2012; Accepted May 30, 2012; Published July 6, 2012 Copyright: ß 2012 Crespo-Enriquez et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    [Show full text]
  • The Duration of Fgf8 Isthmic Organizer Expression Is Key to Patterning Different Tectal-Isthmo-Cerebellum Structures Tatsuya Sato* and Alexandra L
    RESEARCH ARTICLE 3617 Development 136, 3617-3626 (2009) doi:10.1242/dev.041210 The duration of Fgf8 isthmic organizer expression is key to patterning different tectal-isthmo-cerebellum structures Tatsuya Sato* and Alexandra L. Joyner† The isthmic organizer and its key effector molecule, fibroblast growth factor 8 (Fgf8), have been cornerstones in studies of how organizing centers differentially pattern tissues. Studies have implicated different levels of Fgf8 signaling from the mid/hindbrain boundary (isthmus) as being responsible for induction of different structures within the tectal-isthmo-cerebellum region. However, the role of Fgf8 signaling for different durations in patterning tissues has not been studied. To address this, we conditionally ablated Fgf8 in the isthmus and uncovered that prolonged expression of Fgf8 is required for the structures found progressively closer to the isthmus to form. We found that cell death cannot be the main factor accounting for the loss of brain structures near the isthmus, and instead demonstrate that tissue transformation underlies the observed phenotypes. We suggest that the remaining Fgf8 and Fgf17 signaling in our temporal Fgf8 conditional mutants is sufficient to ensure survival of most midbrain/hindbrain cells near the isthmus. One crucial role for sustained Fgf8 function is in repressing Otx2 in the hindbrain, thereby allowing the isthmus and cerebellum to form. A second requirement for sustained Fgf8 signaling is to induce formation of a posterior tectum. Finally, Fgf8 is also required to maintain the borders of expression of a number of key genes involved in tectal- isthmo-cerebellum development. Thus, the duration as well as the strength of Fgf8 signaling is key to patterning of the mid/hindbrain region.
    [Show full text]