Reelin-immunoreactive neurons in the adult vertebrate pallium

Abstract

Reelin, an extracellular matrix protein, plays a crucial role in cortical development. By using Reelin-immunohistochemistry in different vertebrates (fish, amphibians, reptiles, and mammals: insectivores, odontocetes, rodents, carnivores and man) we show here that Reelin is also expressed by a variety of neurons in the adult pallium. In the everted telencephalon of the zebrafish, Reelin-positive neurons are widely distributed over the dorsal pallium. In land vertebrates, the most consistent and evolutionary conserved location of Reelin-expressing neurons is in the cell-sparse molecular layer associated with laminated cortical organization. We describe an additional heterogeneous population of Reelin-positive neurons outside the molecular layer, the location and distribution of which are more variable, and which may reflect major evolutionary changes in cortical architecture. In squamate reptiles, the Reelin-negative main cell layer is flanked by a superficial and a deep plexiform layer which both contain Reelin-expressing neurons. In mammals, Reelin-positive interneurons are dispersed throughout layers II–VI; the human neocortex is particularly poor in Reelin-positive interneurons. Reelin is also expressed by large stellate and modified pyramidal neurons in layer II of the mammalian entorhinal cortex, and in the superficial lateral cortex of lizards. Examination of this cell population (layer II Pre-α) in human brains of different age groups points to a decrease in Reelin-expression in the course of adult life.

Introduction

The extracellular matrix glycoprotein Reelin (Reln) is secreted by a variety of neurons in different brain regions, most prominently by the Cajal-Retzius cells in the marginal zone of the developing mammalian cerebral cortex (D'Arcangelo et al., 1995, Ogawa et al., 1995, D'Arcangelo et al., 1997, Schiffmann et al., 1997, Meyer and Goffinet, 1998). It plays a key role in cortical development, by controlling important aspects of migration and lamination. The target cells of the Reln-signal, the neurons migrating into the cortical plate, express Disabled 1 (Dab1), a cytosolic protein encoded by the disabled-1 gene (Sheldon et al., 1997, Howell et al., 1999). Recent evidence points to a signaling cascade involving Reln, the cell surface proteins’ Very Low Density Lipoprotein Receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2) of the lipoprotein receptor family, and Dab1, which controls the correct positioning of cortical neurons (D'Arcangelo et al., 1999, Hiesberger et al., 1999, Trommsdorff et al., 1999).

The Reln-protein sequence appears to be remarkably conserved during evolution. In accord with its postulated key role during development, Reln is also prominent in corticogenesis of non-mammalian vertebrates such as lizards, turtles and chick, and may have been a driving factor in the evolution of the laminated mammalian neocortex (Bernier et al., 1999, Bernier et al., 2000, Goffinet et al., 1999). The high amplification of the Reln-signal in the fetal human cortex through the subpial granular layer has been related to the dramatic surface increase and complex cytoarchitecture of the human neocortex (Meyer and Goffinet, 1998, Meyer and Wahle, 1999).

In addition to its outstanding developmental role, Reln is also present in the adult brain. In rodent and primate neocortex it is expressed by a heterogeneous collection of GABAergic nonpyramidal cells (Alcántara et al., 1998, Pesold et al., 1998, Pesold et al., 1999, Rodriguez et al., 2000). In the present paper, we examine the expression of Reln in the adult cortex of a wide variety of vertebrates, from the teleostean and amphibian pallia, the most rudimentary forerunners of the mammalian cortex, to the highly differentiated human neocortex. We are particularly interested in the following questions: Is there a basic pattern of Reln-expression, common to the pallium of all vertebrates, and bound to specific cell groups in specific locations? Is there a possible correlation between the evolution of cytoarchitectonic patterns and Reln-expression? Is the adult expression pattern the same as during development? We show that Reln-expressing neurons form part of the neuronal assembly of the adult pallium throughout evolution; furthermore, we suggest that major steps in cortical architecture during evolution are paralleled by changes in the expression pattern of Reln.