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The Role of Organizers in Patterning the Nervous System NE35CH17-Lumsden ARI 14 May 2012 14:25 The Role of Organizers in Patterning the Nervous System Clemens Kiecker and Andrew Lumsden Medical Research Council (MRC) Center for Developmental Neurobiology, King’s College, London SE1 1UL, United Kingdom; email: [email protected], [email protected] Annu. Rev. Neurosci. 2012. 35:347–67 Keywords First published online as a Review in Advance on morphogen signaling, gradients, Spemann, competence, neural tube, March 29, 2012 cell lineage restriction boundaries The Annual Review of Neuroscience is online at neuro.annualreviews.org Abstract This article’s doi: The foundation for the anatomical and functional complexity of the 10.1146/annurev-neuro-062111–150543 by University of Minnesota - Twin Cities on 03/25/13. For personal use only. vertebrate central nervous system is laid during embryogenesis. After Copyright c 2012 by Annual Reviews. Annu. Rev. Neurosci. 2012.35:347-367. Downloaded from www.annualreviews.org Spemann’s organizer and its derivatives have endowed the neural plate All rights reserved with a coarse pattern along its anteroposterior and mediolateral axes, 0147-006X/12/0721-0347$20.00 this basis is progressively refined by the activity of secondary organizers within the neuroepithelium that function by releasing diffusible sig- naling factors. Dorsoventral patterning is mediated by two organizer regions that extend along the dorsal and ventral midlines of the entire neuraxis, whereas anteroposterior patterning is controlled by several discrete organizers. Here we review how these secondary organizers are established and how they exert their signaling functions. Organizer signals come from a surprisingly limited set of signaling factor families, indicating that the competence of target cells to respond to those signals plays an important part in neural patterning. 347 NE35CH17-Lumsden ARI 14 May 2012 14:25 Contents The Zona Limitans INTRODUCTION................. 348 Intrathalamica................. 356 SPEMANN’S ORGANIZER RhombomereBoundaries......... 357 AND EARLY NEURAL COMMON FEATURES OF PATTERNING................. 348 NEUROEPITHELIAL DORSOVENTRAL ORGANIZERS.................. 357 PATTERNING................. 349 Organizers Form Along Cell TheNotochord.................. 351 Lineage Restriction Boundaries 357 The Floor Plate . 351 Positive Feedback Maintains Ventral Neural Patterning by Organizers.................... 357 Shh: A Paradigm for Intrinsic Factors Regulate Morphogen Signaling . 352 Differential Responses to Ventral Patterning in the Organizer Signals . 358 Hindbrain and Midbrain . 352 Hes Genes Prevent Neurogenesis Organizers of Ventral Forebrain in Organizer Regions . 358 Development . 353 NEUROEPITHELIAL TheRoofPlate................... 353 ORGANIZERS ALSO Dorsal Patterning in the Anterior REGULATE Hindbrain.................... 354 PROLIFERATION, TheCorticalHem................ 354 NEUROGENESIS, AND ANTEROPOSTERIOR AXONGUIDANCE............. 358 PATTERNING................. 355 NEUROEPITHELIAL The Midbrain-Hindbrain ORGANIZERS IN Boundary..................... 355 EVOLUTION................... 359 The Anterior Neural CONCLUSIONS................... 360 Boundary/Commissural Plate . 356 INTRODUCTION SPEMANN’S ORGANIZER AND Although it remains astounding, even to the EARLY NEURAL PATTERNING experienced neurobiologist, that a structure as In 1935 Hans Spemann received the Nobel complex as the human brain can arise from a Prize in Medicine for his work with Hilde Man- by University of Minnesota - Twin Cities on 03/25/13. For personal use only. single cell, work in different vertebrate model gold showing that transplantation of a small Annu. Rev. Neurosci. 2012.35:347-367. Downloaded from www.annualreviews.org organisms has started to reveal a network of group of cells from the dorsal blastopore lip tissue and genetic interactions that engineer of a donor embryo to the ventral side of a this extraordinary feat. During embryogenesis, host embryo is sufficient to induce a secondary Dorsal blastopore the primordial neuroepithelium progressively body axis (reviewed in De Robertis & Kuroda lip: a group of dorsal subdivides into distinct regions in a patterning 2004, Niehrs 2004, Stern 2001). Differently mesodermal cells of process governed by small groups of cells pigmented salamander embryos were used as the amphibian embryo that regulate cell fate in surrounding tissues donors and hosts, allowing for an easy distinc- where the involution of mesoderm and by releasing signaling factors. These local tion between cells of graft and host origin. Sur- endoderm starts, signaling centers are called organizers to prisingly, most tissues in the induced second marking the onset reflect their ability to confer identity on axis were derived from the host, suggesting that of gastrulation neighboring tissues in a nonautonomous the graft had induced surrounding tissue to fashion. form axial structures. Thus, Spemann named 348 Kiecker · Lumsden NE35CH17-Lumsden ARI 14 May 2012 14:25 the dorsal blastopore lip the organizer, and tis- fates in a dose-dependent manner such that sues with comparable inductive activity have forebrain, midbrain, hindbrain, and spinal cord since been identified in all vertebrate model or- form at increasing levels of this transformer AP: anteroposterior ganisms and more recently also in some nonver- (Stern 2001). FGFs (Mason 2007), retinoic tebrates (Darras et al. 2011, Meinhardt 2006, acid (Maden 2007), and Wnts all posteriorize DV: dorsoventral Nakamoto et al. 2011). Nowadays the term or- neuroectoderm dose-dependently, but Wnts Bone morphogenetic ganizer is used more widely to describe groups appear to be the best candidates to fulfill this protein (BMP): subfamily of the of cells that can determine the fate of neigh- role in a manner consistent with Nieuwkoop’s transforming growth boring cell populations by emitting molecular model (Kiecker & Niehrs 2001a). Spemann’s factor β superfamily signals. organizer also secretes inhibitors of Wnts, in of secreted signaling The ectopic twin induced in Spemann’s addition to BMP antagonists, and these factors factors; initially experiment contained a complete CNS that remain expressed in the anterior AME but identified by their promotion of bone and was properly patterned along its anteropos- are absent from the posterior AME during cartilage formation terior (AP, head-to-tail) and dorsoventral gastrulation (Kiecker & Niehrs 2001b). Thus, Fibroblast growth (DV, back-to-belly) axes, indicating that the the Spemann-Mangold model of regionally factor (FGF): organizer harbors both neural-inducing and specific inductions and Nieuwkoop’s gradient- secreted signaling neural-patterning activities. More recently, a based model turn out to be two sides of the molecules that signal large number of factors that are expressed in same coin: The anterior AME induces the via tyrosine kinase Spemann’s organizer have been identified, and forebrain by acting as a sink for posteriorizing receptors several were found to be secreted inhibitors Wnts. Wnts: secreted of bone morphogenetic proteins (BMPs). In lipid-modified glycoproteins that combination with other findings in frog and regulate multiple fish embryos, this led to a model whereby aspects of Spemann’s organizer induces the neural plate DORSOVENTRAL PATTERNING embryogenesis and in the dorsal ectoderm by inhibiting BMPs, The ectoderm that surrounds the neural plate adult homeostasis by whereas the ventral ectoderm forms epidermis expresses BMPs while Spemann’s organizer and activating several different signaling because it remains exposed to BMPs (De the extending AME express BMP inhibitors. pathways Robertis & Kuroda 2004, Munoz-Sanju˜ an´ Experiments in zebrafish embryos have sug- AME: axial & Brivanlou 2002). Experiments in chick gested that this generates a gradient of BMP ac- mesendoderm embryos have since added complexity to tivity that defines mediolateral positions within this default model for neural induction by the neural plate (Barth et al. 1999). Hence, a implicating other signaling proteins such as Cartesian coordinate system of two orthogonal fibroblast growth factors (FGFs) and Wnts as gradients is established—a Wnt gradient along additional neural inducers (Stern 2006). the AP axis and a BMP gradient along the medi- by University of Minnesota - Twin Cities on 03/25/13. For personal use only. During gastrulation, the organizer re- olateral axis—and the AME defines the origin Annu. Rev. Neurosci. 2012.35:347-367. Downloaded from www.annualreviews.org gion stretches out and gives rise to the axial of this system by secreting BMP and Wnt an- mesendoderm (AME), which comes to under- tagonists (Figure 1a) (Meinhardt 2006, Niehrs lie the midline of the neural plate along its 2010). It is clear that such global mechanisms AP axis. Otto Mangold found that different can establish only a crude initial pattern, and AP regions of the AME induced different we argue below that this pattern is increasingly parts of the embryonic axis when grafted refined through the establishment of local (or into host embryos, leading to the idea of secondary) organizers in the neuroepithelium. regionally specific inductions by the organizer Gastrulation is followed by neurulation dur- (Niehrs 2004). This model was challenged in ing which the lateral folds of the neural plate the 1950s when Nieuwkoop and others pro- roll up and fuse to form the neural tube posed that the CNS is patterned by a gradient (Figure 1b,c). Thus, the initial mediolateral of a transformer that travels within the plane pattern
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