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Early Rostrocaudal Patterning of the CNS
Umeå University, Faculty of Medicine, Molecular Biology.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The transformation of an initially uniform population of epiblast cells into an intricately complex central nervous system (CNS) is one of the most fascinating processes during embryonic development. Presumptive neural cells are initially specified as cells of forebrain character. Studies in various vertebrates have indicated that cells of more caudal neural character, that will generate the brain stem and spinal cord, are generated through the reprogramming of these initial rostral cells. The initial regionalization of these neural progenitor cells is central to all further diversification of neuronal cell types and the subsequent formation of functional euronal circuits. The aim of this thesis has been to enhance our understanding of which stages of embryonic development that are critical for the initial rostrocaudal regionalization of neural precursor cells, and which signaling mechanisms that orchestrate this early diversification.

Both human and chick embryos have the shape of a flat disc during gastrulation. At this early stage, the chick neural plate is already regionalized and cells positioned at distinct rostrocaudal levels are specified to generate cells exhibiting a gene expression profile characteristic of the forebrain, midbrain, rostral hindbrain and caudal spinal cord, respectively. In addition, the Isthmic organizer (IsO), a secondary signaling centre at the midbrain–hindbrain border that is required for the further development of this region, is also specified already at the gastrula stage. Caudal neural character is induced by signals from adjacent tissues - the primitive streak and the paraxial mesoderm. Wingless/Wnts, Fibroblastic growth factors (FGFs) and retinoids (RA) are signaling molecules that have been proposed to promote caudal embryonic development, and exhibit spatio- emporal expression patterns that coincide with early caudalizing activities. The caudalizing activity that emanates from the gastrula stage paraxial mesoderm is mediated by Wnt signals, and the induction of caudal neural character by Wnts results from a direct action on neural precursor cells. In the presence of FGF activity, graded Wnt signaling is sufficient to induce cells exhibiting caudal forebrain, midbrain and rostral hindbrain character. The discrimination between rostral hindbrain and caudal spinal cord character appear to depend on a gradient of both Wnt and FGF signals.

At hindbrain and spinal cord levels the patterned generation of neural progenitor cells along the rostrocaudal axis controls the generation of different classes of motor neurons in response to diffusible Sonic hedgehog (Shh) signals. Gastrula stage Wnt signaling is also required for this subsequent generation of motor neuron subtypes characteristic of the hindbrain and spinal cord.

Later, at the early somite stage, cells characteristic of the caudal hindbrain and rostral spinal cord are specified adjacent to RA producing paraxial mesoderm. Opponent RA and FGF signals appear to act on, and refine the rostrocaudal identity of the initial hindbrain and spinal cord cells induced by gastrula stage Wnt based signals. Consistently, combinatorial Wnt, FGF and/or RA signals are sufficient to reconstruct neural progenitor cells that differentiate into motor neurons characteristic of the caudal hindbrain, rostral spinal cord and caudal spinal cord, respectively, in response to Shh.

Abstract [sv]

Transformationen av en initialt uniform cellpopulation till något så komplext som det centrala nervsystemet (CNS) är en av de mest fascinerande processerna under fosterutvecklingen. Anlaget till neuronala celler är initialt programmerade att generera nervceller som är typiska för den blivande hjärnan (cerebrum). Forskning på olika vertebrata modell-organsimer har klargjort att nedre regioner av CNS, hjärnstammen lillhjärnan och ryggmärgen, genereras genom reprogrammering av dessa initiala celler. Målet med avhandlingsarbetet har varit att öka förståelsen för vilka perioder under fosterutveckingen som är kritiska för den initiala induktionen av neuronala celltyper som är specifika för dessa olika regioner, samt vilka signalerings mekanismer som styr den initiala re-programmeringen.

Under gastruleringen bildar anlaget till neuronala celler en, till synes uniform, platta medialt i ektodermet i både humana-, och kyckling embryon. Anlaget till neuronal vävnad är dock redan under detta tidiga utvecklingsstadie indelat i regioner. Celler inom en specifik region är programmerade att generera celler med en genexpressions-profil som är specifik för anlaget till hjärnan, de övre delarna av hjärnstammen (diencephalon, mesencephalon, metencephalon) eller den nedre delen av ryggmärgen. Även Isthmus – ett sekundärt organisations centra som bildas i konstriktionen mellan mesencephalon och metencephalon, och som behövs för den senare utvecklingen av dessa regioner – specificeras redan på gastrula stadiet.

Dessa nedre neuronala celltyper induceras av signal molekyler från närliggande vävnader som t.ex. primitivstrimman och det paraxiala mesodermet. Wingless/Wnt, Fibroblast tillväxtfaktorer (FGFs) samt vitamin A metaboliter (retinoider, RA) är exempel på signalmolekyler som påverkar de nedre vävnaderna under tidig embryonal utveckling. Dessutom indikerar spatialt och temporalt reglerade genexpressionsmönster att närvaro av dessa signalerings proteiner sammanträffar med när och var nedre neuronala celltyper specificeras. Den signal aktivitet som avges från det paraxiala mesodermet i det gastrulerande embryot medieras av Wnt signalering. För induktion av nedre neuronala identiteter krävs Wnt signalering i de presumtivt neuronala cellerna.

I närvaro av FGF signalerings aktivitet är det tillräckligt med en stigande gradient av Wnt signalering för att succesivt generera celler med en genexpressions profil som är specifik för diencephalon, mesencephalon och metencephalon. Distinktionen mellan, metencephalon och nedre ryggmärgs identitet verkar vara resultatet av en gradient av både Wnt och FGF signalering.

När det paraxiala mesodermet börjar bilda somiter har även celler med en genexpressions-profil som är specifik för den förlängda märgen (myelencephalon) och den övre delen av ryggmärgen blivit specificerade. Dessa celltyper bildas i regioner där det närliggande paraxiala mesodermet producerar RA. En gradient av Wnt och FGF signalering ger upphov till en initial nedre celltyps identitet som krävs för att dessa celler ska kunna svara på RA signaleringen. Antagoniserande aktiviteter av RA och FGF signalering avgör vilka celler som sedermera kommer att ge upphov till förlängda märgen eller övre-, respektive, nedre ryggmärgen.

Senare under utvecklingen bildas olika regionspecifika klasser av motorneuroner i bla. förlängda märgen och ryggmärgen. Den initiala, Wnt medierade, regionaliseringen av neuronala celltyper är central även för denna process. Dessutom kan olika klasser av motorneuroner, specifika för den förlängda märgen, respective övre-, och nedre ryggmärgs regionerna, rekonstrueras in vitro genom att reprogrammera naivt neuroepitel mha. en kombination av Wnt, RA och/eller FGF.

Place, publisher, year, edition, pages
Umeå: Molekylärbiologi (Teknisk-naturvetenskaplig fakultet) , 2005. , 76 p.
Keyword [en]
CNS development, neural patterning, neural specification, Wnt, FGF, RA, Isthmic organizer, motor neurons, rostrocaudal patterning.
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:umu:diva-614ISBN: 91-7305-940-4 (print)OAI: oai:DiVA.org:umu-614DiVA: diva2:143990
Public defence
2005-11-11, 09:00 (English)
Supervisors
Available from: 2005-10-19 Created: 2005-10-19 Last updated: 2009-12-18Bibliographically approved
List of papers
1. Progressive induction of caudal neural character by graded Wnt signaling
Open this publication in new window or tab >>Progressive induction of caudal neural character by graded Wnt signaling
2002 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 5, no 6, 525-532 p.Article in journal (Refereed) Published
Abstract [en]

Early in differentiation, all neural cells have a rostral character. Only later do posteriorly positioned neural cells acquire characteristics of caudal forebrain, midbrain and hindbrain cells. Caudalization of neural tissue in the chick embryo apparently involves the convergent actions of (i) fibroblast growth factor (FGF) signaling and (ii) signaling from the caudal paraxial mesoderm, or 'PMC activity', which has not yet been defined molecularly. Here we report evidence that Wnt signaling underlies PMC activity, and show that Wnt signals act directly and in a graded manner on anterior neural cells to induce their progressive differentiation into caudal forebrain, midbrain and hindbrain cells.

Identifiers
urn:nbn:se:umu:diva-4757 (URN)10.1038/nn0602-854 (DOI)12006981 (PubMedID)
Available from: 2005-10-19 Created: 2005-10-19 Last updated: 2017-12-14Bibliographically approved
2. Convergent Wnt and FGF signaling at the gastrula stage induce the formation of the isthmic organizer.
Open this publication in new window or tab >>Convergent Wnt and FGF signaling at the gastrula stage induce the formation of the isthmic organizer.
2006 (English)In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 123, no 2, 166-176 p.Article in journal (Refereed) Published
Abstract [en]

The development of the vertebrate brain depends on the formation of local organizing centres within the neural tube that express secreted signals that refine local neural progenitor identity. The isthmic organizer (IsO) forms at the isthmic constriction and is required for the growth and ordered development of mesencephalic and metencephalic structures. The formation of the IsO, which is characterized by the generation of a complex pattern of cells at the midbrain-hindbrain boundary, has been described in detail. However, when neural plate cells are initially instructed to form the IsO, the molecular nature of the inductive signals remain poorly defined. We now provide evidence that convergent Wnt and FGF signaling at the gastrula stage are required to generate the complex polarized pattern of cells characteristic of the IsO, and that Wnt and FGF signals in combination are sufficient to reconstruct, in naïve forebrain cells, an IsO-like structure that exhibits an organizing activity that mimics the endogenous IsO when transplanted into the diencephalon of chick embryos.

Keyword
Animals, Body Patterning, Chick Embryo, Fibroblast Growth Factors/*metabolism, Gastrula/*metabolism, Mesencephalon/cytology/*embryology/metabolism, Prosencephalon/cytology/metabolism, Rhombencephalon/cytology/*embryology/metabolism, Signal Transduction, Wnt Proteins/*metabolism
Identifiers
urn:nbn:se:umu:diva-5814 (URN)10.1016/j.mod.2005.11.001 (DOI)16413176 (PubMedID)
Available from: 2007-11-30 Created: 2007-11-30 Last updated: 2017-12-14Bibliographically approved
3. Early Wnt Signaling is Required to Establish Hox Gene Profiles and Motor Neuron Subtypes in the Developing Hindbrain and Spinal Cord
Open this publication in new window or tab >>Early Wnt Signaling is Required to Establish Hox Gene Profiles and Motor Neuron Subtypes in the Developing Hindbrain and Spinal Cord
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4759 (URN)
Available from: 2005-10-19 Created: 2005-10-19 Last updated: 2010-01-13Bibliographically approved

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