Elsevier

Brain Research Reviews

Volume 43, Issue 2, October 2003, Pages 179-191
Brain Research Reviews

Review
Neuroepithelial secondary organizers and cell fate specification in the developing brain

https://doi.org/10.1016/j.brainresrev.2003.08.002Get rights and content

Abstract

In vertebrates, elaborate cellular interactions regulate the establishment of the complex structural pattern of the developing central nervous system. Distinct neural and glial identities are acquired by neuroepithelial cells, through progressive restriction of histogenetic potential under the influence of local environmental signals. The localization of the sources of such morphogenetic signals in discrete domains of the developing neural primordium has led to the concept of secondary organizers which refine the identity and polarity of neighboring neuroepithelial regions. Thus, these organizers, secondary to those that operate throughout the embryo during gastrulation, act to pattern the anterior neural plate and tube giving rise to the forebrain, midbrain and hindbrain vesicles. Important progress has recently been made in understanding their genesis and function.

Introduction

The organization of the central nervous system (CNS) in vertebrates arises from the concerted action of morphogenetic signals during the early gastrula stage of embryonic development. At this stage, the embryo is regionalized into three germ layers: the ectoderm, the mesoderm and the endoderm. In the ectoderm, the neural plate is induced by the interaction of vertical and planar signals emanating from the node (The Spemann-Mangold organizer) and the perineural ectoderm, as well as from the ventral endoderm and axial mesoderm [12], [122]. Complex combinations of inductive influences from these primary organizers regulate the establishment of the antero-posterior and medio-lateral polarity of the embryo during gastrulation. After neural induction, during the process of neurulation, the edges of the neural plate thicken and fold upwards to form the neural folds, which then progress towards the dorsal midline and fuse, thus creating the neural tube. At this point, the original medio-lateral polarity of the neural plate becomes the ventro-dorsal polarity of the neural tube. Prior to the fusion of the neural folds at the anterior neuropore, the longitudinal axis of the neural plate intersects what will later become the ventro-dorsal axis at the anterior-most end of the neural tube. This intersection represents the anterior radial axis of the neural plate [99], [110], [117], [118] (Fig. 1A).

The ventro-dorsal axis is determined by the antagonistic interaction between ventralizing factors such as Sonic hedgehog (Shh) produced in the notochord and ventral midline of the neuroectoderm (i.e. the floor plate Fig. 1B) [65], [107], [108] and dorsalizing factors like members of the bone morphogenetic protein (BMP) family which emanate from the adjacent non-neural ectoderm [58]. Thus, the neural tube is divided symmetrically into four types of longitudinal domains with distinct gene expression patterns and morphological properties: the floor plate, the basal plate, the alar plate and the roof plate (Fig. 1A,B). These domains are characterized by the expression of Shh (floor plate; [29]), Nkx2.2 (ventro-lateral domain at the basal-alar boundary) [94], [97] and Noggin and Wnt1 (the roof plate) [55], [92]; for review, see Ref. [118] Fig. 1, Fig. 2.

The great structural heterogeneity of the brain along its antero-posterior axis reflects a high degree of complexity in the process of regional specification. Initial antero-posterior identities in the neural plate are specified early in development during the process of neural induction. This takes place in response to a sequential pattern of signals from the proximal edges of the epiblast and primitive endoderm, which upon gastrulation give rise to the anterior visceral endoderm or mesendoderm, as well as from the node and the other primary organizers [11], [12], [69], [122]. Then, at neural plate and tube stages, local signaling centers in the neuroepithelium, known as secondary organizers, refine the antero-posterior specification of three main domains in the brain primordium; the prosencephalon or forebrain, the mesencephalon or midbrain and the rhombencephalon or hindbrain (see for review Ref. [111]). Additionally, the morphogenetic activity of the secondary organizers controls the polarity and the generation of neural sub-regions inside these main regions [23], [66], [68], [73], [118].

In this review we discuss the latest findings regarding the secondary organizers which have been described as focal transverse domains with morphogenetic activity along the antero-posterior axis of the neural tube. The recent combination of genetic and experimental embryological approaches using mouse and chick embryos has resulted in tremendous progress in understanding the formation and function of these local signaling centers. We will describe our current knowledge about molecules responsible for the morphogenetic activity of the organizers and as far as possible the factors that mediate the corresponding cell fate specifications.

Three regions in the neural plate and tube have been identified as putative secondary organizers: the anterior neural ridge (ANR) at the anterior end of the neural plate, the zona limitans intrathalamica (ZLI) in the middle of the diencephalon and the isthmic organizer (IsO) at the mid–hindbrain transition (Fig. 1C). In the following sections we will describe their cellular and molecular properties.

Section snippets

The anterior neural ridge (ANR)

The vertebrate forebrain (prosencephalon) is derived from the anterior neural plate. There is mounting evidence that at neural plate stages, the neuroepithelium already has anterior properties. Recent studies of the process of gastrulation in mouse have shown that the initiation and regulation of anterior patterning of the neural plate depends on vertical inductive influences from the anterior visceral endoderm, which ultimately contributes to extraembryonic tissues, and the node [26], [47],

The zona limitans intrathalamica (ZLI)

The zona limitans intrathalamica (ZLI) is a neuroepithelial site in the diencephalon which has recently been considered as a possible source of local morphogenetic properties Fig. 1, Fig. 2. The process of morphological segmentation in the diencephalon starts at E9.5 in the mouse and HH 10–11 in the chick [13], [33], [42], [46], [68], [131]. The diencephalon is localized between two transversal boundaries; its rostral boundary lies between the pedunculo-mammillary region (part of the secondary

The isthmic organizer (IsO)

The isthmus is a neural region localized at the mid–hindbrain transition and represents the most anterior segment of the rhombencephalon or hindbrain Fig. 1, Fig. 4, Fig. 5. The isthmic organizer (IsO) is localized in the isthmic territory and is also known as the mid–hindbrain organizer (MHO). However, we prefer to use the term IsO, since the organizer activity is not exclusively localized in the mid–hindbrain boundary (i.e. the anterior limit of the isthmus; Fig. 4A). By means of studies of

Concluding remarks

The present work has overviewed current knowledge of three focal transverse sources of morphogenetic activity in the developing brain: the ANR, ZLI and IsO. These secondary organizers, already determined before neurulation, secrete local cues that refine neural tube domains into the definitive neural structures of the CNS. We have described how these regions express similar morphogenes, which appear to activate and induce cell processes in the neighboring tissue, ultimately specifying regional

Acknowledgements

We would like to thank Dr. Alfredo Varela-Echevarrı́a and Dr. Constantino Sotelo for helpful comments on this review. The work presented by the authors has been supported by the following: European Union Grants U.E. QLG2-CT-1999-00793; UE QLRT-1999-31556; UE QLRT-1999-31625; QLRT-2000-02310; Spanish Grants DIGESIC-MEC PM98-0056; FEDER-1FD97-2090; Basque Government fellowship BIF00.80.DE; Seneca Foundation; Francisco Cobos Foundation; Iberdrola Enterprise, the Spanish Multiple Sclerosis

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