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Induction of the isthmic organizer and specification of the neural plate border
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The vertebrate nervous system is extremely complex and contains a wide diversity of cell types. The formation of a functional nervous system requires the differential specification of progenitor cells at the right time and place.

The generation of many different types of neurons along the rostro-caudal axis of the CNS begins with the initial specification of a few progenitor domains. This initial coarse pattern is refined by so-called secondary organizers arising at boundaries between these domains. The Isthmic Organizer (IsO) is a secondary organizer located at the boundary between the midbrain and the hindbrain. Although the function and maintenance of the IsO are well understood, the processes underlying its initial specification have remained elusive. In the present work we provide evidence that convergent Wnt and FGF signals initiate the specification of the IsO during late gastrulation as part of the neural caudalization process.

The initial step in the generation of the nervous system is the division of the embryonic ectoderm into three cell populations: neural cells giving rise to the CNS, neural plate border cells giving rise to the peripheral nervous system, and epidermal cells giving rise to the outer layer of the skin. While the choice between neural and epidermal fate has been well studied, the mechanism by which neural plate border cells are generated is less well understood. At rostral levels of the neuraxis, the neural plate border gives rise to the olfactory and lens placodes, thickenings of the surface ectoderm from which sensory organs are derived. More caudally, the neural plate border generates neural crest cells, a transient population that migrates extensively and contributes to neurons and glia of the peripheral nervous system. How the early patterning of the central and peripheral nervous systems are coordinated has remained poorly understood. Here we show that the generation of neural plate border cells is initiated at the late blastula stage and involves two phases. During the first phase, neural plate border cells are exposed to Wnt signals in the absence of BMP signals. Simultaneous exposure to Wnt and BMP signals at this early stage leads to epidermal induction. Wnt signals induce expression of Bmp4, thereby regulating the sequential exposure of cells to Wnt and BMP signals. During the second phase, at the late gastrula stage, BMP signals play an instructive role to specify neural plate border cells of either placodal or neural crest character depending on the status of Wnt signaling. At this stage, Wnt signals promote caudal character simultaneously in the neural plate border and in the neural ectoderm. Thus, the choice between epidermal and neural plate border specification is mediated by an interplay of Wnt and BMP signals that represents a novel mechanism involving temporal control of BMP activity by Wnt signals. Moreover, the early development of the central and peripheral nervous systems are coordinated by simultaneous caudalization by Wnt signals.

Place, publisher, year, edition, pages
Umeå: Umeå centrum för molekylär medicin (UCMM) , 2008. , 81 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1197
Keyword [en]
neural plate border, neural crest, placodes, Isthmic organizer, Wnt, BMP, FGF
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-1811ISBN: 978-91-7264-603-2 (print)OAI: oai:DiVA.org:umu-1811DiVA: diva2:142071
Public defence
2008-09-26, Major Groove, 6L, Umeå Universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2010-01-18Bibliographically approved
List of papers
1. 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, 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: 2009-11-25Bibliographically approved
2. Early development of the central and peripheral nervous systems is coordinated by Wnt and BMP signals
Open this publication in new window or tab >>Early development of the central and peripheral nervous systems is coordinated by Wnt and BMP signals
2008 (English)In: PloS one, ISSN 1932-6203, Vol. 3, no 2, e1625- p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-3394 (URN)18286182 (PubMedID)
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2011-04-06Bibliographically approved
3. Wnt-regulated temporal control of BMP exposure directs the choice between neural plate border and epidermal fate
Open this publication in new window or tab >>Wnt-regulated temporal control of BMP exposure directs the choice between neural plate border and epidermal fate
2009 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 136, no 1, 73-83 p.Article in journal (Refereed) Published
Abstract [en]

The non-neural ectoderm is divided into neural plate border and epidermal cells. At early blastula stages, Wnt and BMP signals interact to induce epidermal fate, but when and how cells initially acquire neural plate border fate remains poorly defined. We now provide evidence in chick that the specification of neural plate border cells is initiated at the late blastula stage and requires both Wnt and BMP signals. Our results indicate, however, that at this stage BMP signals can induce neural plate border cells only when Wnt activity is blocked, and that the two signals in combination generate epidermal cells. We also provide evidence that Wnt signals do not play an instructive role in the generation of neural plate border cells, but promote their generation by inducing BMP gene expression, which avoids early simultaneous exposure to the two signals and generates neural plate border instead of epidermal cells. Thus, specification of neural plate border cells is mediated by a novel Wnt-regulated BMP-mediated temporal patterning mechanism.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-3395 (URN)10.1242/dev.025890 (DOI)19060333 (PubMedID)
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2012-08-10Bibliographically approved

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