Trends in Neurosciences
Divide et Impera – the midbrain–hindbrain boundary and its organizer
Section snippets
Genetic architecture of the organizer
The organizer potential of the MHO was first demonstrated in classical grafting experiments in chick showing that MHB tissue, when transplanted to more anterior (diencephalic) or posterior (rhombencephalic) positions, could stimulate the development of ectopic midbrain or cerebellum structures, respectively [6]. Subsequently, molecular and genetic analyses began to uncover the genetic framework underlying formation of the MHB and its organizer potential. Early neural patterning leads to the
Orchestrating brain development: signals and cues
How can cells of the MHO influence the surrounding tissues? Several secreted proteins are expressed at the midbrain–hindbrain junction. These include members of the wingless/Wnt (Wnt1, Wnt8b) and fibroblast growth factor (FGF8, FGF17, FGF18) families, as well as other secreted molecules such as isthmin [30] (F. Raible, I. Araki and M.Brand, unpublished). Out of this cocktail, Wnt proteins have been associated mostly with proliferative control (as will be discussed later in this review), whereas
Shaping territories: linking molecular patterns and morphogenesis
The mechanisms that generate distinct gene expression patterns in the midbrain–hindbrain area do not necessarily explain how these ‘blueprints’ are translated into the elaborate morphological structures that arise from the alar and roof plate of this region, such as the isthmic constriction, the tectal lobes of the midbrain or, posteriorly, the cerebellar hemispheres and vermis. At the cellular level, selected regulation of proliferation, cell death, adhesion or mobility must account for these
Checks and balances: controlling the organizer activity
An emerging topic of MHO research has been to understand how the powerful inducing ability of the MHO is properly tuned in time and space. At the cell biological level, one important line of research focuses on regulation of the FGF-dependent mitogen-activated protein kinase (MAPK) pathway. Factors that affect this pathway are likely to play a role in modulating midbrain–hindbrain development. Spatial and temporal co-expression of genes (‘synexpression’) is an indicator of functional
Impact of the MHO on neural organization
Functional specialization of midbrain and cerebellum requires the regulation of neural differentiation, migration and connectivity. One basic level of control revolves around the distinction between neurogenic and non-neurogenic brain areas. The isthmic primordium itself remains a zone of delayed differentiation (reviewed in Ref. [60]). The transcription factor Her5 is expressed in the zebrafish MHB in a similar way to, but independent of, Pax2 [61]. Interference experiments in suggest that
The rise and change of MHO activity in development and evolution
The midbrain–hindbrain junction and, later, the isthmus have a prominent role in distinct processes over a long period of brain development. In many instances, FGFs have been associated with these functional effects, underscoring the potent and versatile function of this molecule class. In turn, the repetitive use of the same signalling molecules reflects the differences in the molecular ‘interpretation’ of this signal by the target tissue. Therefore, ‘the organizer’ can hardly be viewed in
Acknowledgements
We appreciate the critical feedback from Kristin Tessmar-Raible, József Jászai, Gerlinde Reim and Muriel Rhinn, as well as from the anonymous reviewers, on the manuscript. We apologize to colleagues whose work could not be cited owing to space constraints, and we refer readers to the quoted reviews for many older and/or primary references. Our research was supported by grants from the Max-Planck Society and the European Union (QLG3-CT-2001–02310; M.B.) and by a scholarship of the German
References (74)
- et al.
Patterning the vertebrate neuraxis
Science
(1996) - et al.
Early steps in the development of the forebrain
Dev. Cell
(2004) Otx2, Gbx2 and Fgf8 interact to position and maintain a mid–hindbrain organizer
Curr. Opin. Cell Biol.
(2000)- et al.
The midbrain–hindbrain boundary organizer
Curr. Opin. Neurobiol.
(2001) - et al.
Neural plate patterning: upstream and downstream of the isthmic organizer
Nat. Rev. Neurosci.
(2001) The midbrain–hindbrain junctsion: a model system for brain regionalization through morphogenetic neuroepithelial interactions
A role for Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer
Nature
(1999)The caudal limit of Otx2 expression positions the isthmic organizer
Nature
(1999)Interaction between Otx2 and Gbx2 defines the organizing center for the optic tectum
Mech. Dev.
(2000)Midbrain development induced by FGF8 in the chick embryo
Nature
(1996)