Key Points
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Local signalling centres are important in patterning the neural axis. The isthmic organizer (IsO), which lies at the junction between the midbrain and hindbrain, is one of these signalling centres. The IsO participates in the development of mesencephalic and metencephalic structures.
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Transplantation experiments led to the identification of the IsO and have provided the best evidence of its organizing activity. Grafting tissue from the mid-hindbrain junction to ectopic sites induced mes-metencephalic fates and gene expression patterns in the host tissue. The induced tissue showed the same polarity as that observed in the intact brain.
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Gene expression patterns at the mes-metencephalic junction have helped to define its molecular identity. The early expression of the transcription factors Otx2 and Gbx2 seems to define the prospective mesencephalic and metencephalic domains, respectively. The border between the expression territories of these two molecules positions the IsO in the embryo, an idea supported by genetic and embryological experiments.
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At later developmental stages, other molecules are expressed at the mid-hindbrain junction. They include members of the En and Pax families of transcription factors, as well as the secreted molecules Fgf8 and Wnt1. Although the expression of all of these molecules is necessary for the development of the midbrain and hindbrain, Fgf8 has received the most attention as the mediator of IsO activity.
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The ectopic delivery of Fgf8 partly mimics the effect of IsO grafts. It has been proposed that Fgf8 does not induce an ectopic organizer but it participates in the positive loop that maintains the IsO and transduces its activity. At the same time, the activity of the IsO is controlled by a negative regulatory loop that is triggered by the IsO itself, as well as by negative influences from the neighbouring tissues.
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An interplay between dorsoventral and anteroposterior signals is probably required for the development of specific neuronal sub-populations in the midbrain and hindbrain. The generation of dopamine and noradrenaline neurons probably results from the concerted action of dorsoventral signals from the IsO and molecules involved in anteroposterior patterning, such as Sonic hedgehog or members of the BMP family.
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What factors induce the expression of Otx2 and Gbx2, the earliest mes-metencephalic markers? What is the function of Wnt1 in the mid-hindbrain domain? What factors determine the polarity of tissue induced by the IsO? These questions still await an answer and constitute some of the future directions in this expanding field.
Abstract
Two organizing centres operate at long-range distances within the anterior neural plate to pattern the forebrain, midbrain and hindbrain. Important progress has been made in understanding the formation and function of one of these organizing centres, the isthmic organizer, which controls the development of the midbrain and anterior hindbrain. Here we review our current knowledge on the identity, localization and maintenance of the isthmic organizer, as well as on the molecular cascades that underlie the activity of this organizing centre.
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Acknowledgements
We thank J.-F. Nicolas, M. Wassef and members of our laboratories for stimulating discussions on this topic, and A. Joyner, S. Martinez, A. Simeone and M. Wassef for sharing results before publication. Work in our laboratories is supported by the HFSP (W.W.), EUBiotech2 programme (W.W.) and the Volkswagen Stiftung (L. B.-C.)
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Glossary
- EPIBLAST
-
The outer layer of a blastula that gives rise to the ectoderm after gastrulation.
- GASTRULA
-
Embryo that is in the process of regionalizing into three germ layers (ectoderm, mesoderm and endoderm).
- TELEOST
-
Group of fish with bony skeletons.
- PROSENCEPHALON
-
The most rostral of the primary vesicles that are present in the early neural tube, which later gives rise to two secondary vesicles: telencephalon (prospective cerebral hemispheres) and diencephalon (prospective thalamus, hypothalamus).
- RHOMBENCEPHALON
-
The most caudal of the primary vesicles that are present in the early neural tube, which later gives rise to two secondary vesicles: metencephalon (prospective pons and cerebellum) and myelencephalon (prospective medulla oblongata).
- FLOOR PLATE
-
The neural tube has been divided in different regions. The ventral cells closest to the midline constitute the floor plate. The dorsal cells closest to the midline correspond to the roof plate. The alar plate (dorsal) and the basal plate (ventral) lie between these two cell populations and are separated by the sulcus limitans.
- BONE MORPHOGENETIC PROTEINS
-
Molecules of the TGF-β family involved in the production of bone and cartilage, and important regulators of dorsoventral patterning.
- NOTOCHORD
-
Rod-like structure of mesodermal origin found in vertebrate embryos, which participates in the differentiation of the ventral neural tube and in the specification of ventral neurons.
- CLONAL RESTRICTION
-
Restriction of all the progeny of a given ancestor cell to a spatially limited territory.
- SOMITES
-
Paired blocks of mesoderm cells along the vertebrate body axis that form during early vertebrate development and differentiate into dermal skin, bone and muscle.
- MES-METENCEPHALIC JUNCTION
-
Refers to the narrow territory where the isthmic organizer is localized, and should not be confused with mes-metencephalic domain, which comprises the whole mesencephalic and metencephalic regions. Similarly, the term mid-hindbrain domain should be understood as mes-metencephalic domain, and not as referring to the whole midbrain and hindbrain areas.
- PROSOMERE
-
Each of the six subdivisions thought to compose the embryonic forebrain, defined by their specific patterns of gene expression. Prosomeres 1–3 constitute the diencephalon, whereas prosomeres 4–6 comprise the hypothalamus and the telencephalon.
- RHOMBOMERE
-
Each of seven neuroepithelial segments found in the embryonic hindbrain that adopt distinct molecular and cellular properties, restrictions in cell mixing and ordered domains of gene expression.
- NEURULATION
-
Morphogenetic process during which the progenitors of the nervous system segregate from the ectoderm.
- HOMEODOMAIN-CONTAINING PROTEINS
-
Transcription factors with a 60 amino acid DNA-binding domain comprised of three α-helices.
- NEUROMERES
-
Series of swellings and constrictions along the neural tube at early stages of embryonic development, which constitute evidence of the intrinsic segmentation in the nervous system.
- ZONA LIMITANS INTRATHALAMICA
-
Embryonic structure that determines the limit between dorsal and ventral thalamus.
- VERMIS
-
Cerebellar structure located at the midline involved in maintaining posture and the control of eye movement.
- RAPHE NUCLEI
-
Brainstem structures that constitute the main supply of serotonin to the rest of the brain.
- LOCUS COERULEUS
-
Brainstem nucleus that constitutes the main supply of noradrenaline to the rest of the brain.
- DOMINANT-NEGATIVE PROTEIN
-
A mutant molecule capable of antagonizing the function of its endogenous counterpart.
- GAP JUNCTIONS
-
Cellular junctions that allow the free passage of small molecules through non-selective channels called connexons.
- CEREBELLAR PLATE
-
Structure that constitutes the cerebellar primordium. It is formed by the fusion of the rhombic lips at the midline.
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Wurst, W., Bally-Cuif, L. Neural plate patterning: Upstream and downstream of the isthmic organizer . Nat Rev Neurosci 2, 99–108 (2001). https://doi.org/10.1038/35053516
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