Consequences of Neural Cell Adhesion Molecule Deficiency on Cell Migration in the Rostral Migratory Stream of the Mouse

Abstract

In vertebrates, interneurons of the olfactory bulb (OB) are generated postnatally and throughout life at the subventricular zone of the forebrain. The neuronal precursors migrate tangentially through the forebrain using a well defined pathway, the rostral migratory stream (RMS), and a particular mode of migration in a chain-like organization. A severe size reduction of the OB represents the most striking morphological phenotype in neural cell adhesion molecule (NCAM)-deficient mice. This defect has been traced back to a migration deficit of the precursors in the RMS and linked to the lack of the polysialylated form of NCAM. In this study we investigate the morphological alterations and functional properties of the RMS in mice totally devoid of all isoforms of NCAM and polysialic acid (PSA). We show that a morphologically altered, but defined and continuous pathway exists in mutants, and we present in vivo and in vitro evidence that PSA-NCAM in the RMS is not essential for the formation and migration of chains. Instead, we find a massive gliosis associated with the formation of membrane specializations in a heterotypic manner, linking precursors to astrocytes. This finding and the over-representation and defasciculation of axons in the pathway suggest that important interactions between migrating cells and their stationary environment are perturbed in the mutants. Finally, we used transplantation experiments to demonstrate that lack of PSA-NCAM leads to a decrease but not a total blockade of migration and demonstrate that the mutant RMS is functional in transporting normal neuronal precursors to the OB.

Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain

“…This may lead to a blockage of neuronal migration in the RMS that is 13 partially cell-autonomous and partially non-cell autonomous. As DCX is clearly not expressed in glia of the RMS, the increase in number of glia and malorientation of these cells relative to the direction of the RMS may reflect glial proliferation in response to stalled neuronal migration, as has been reported in the NCAM mutant resulting in a similar phenotype 22 .…”

“…Parasagittal sections from adult mice (P49-56) through the SVZa, RMS and OB were stained using Cresyl violet to delineate the cell-dense RMS 22 . Surprisingly, we found a significant alteration in the morphology of the SVZa and RMS, with these structures approximately doubled in thickness along much of their length.…”

“…Mutations in the transcriptional regulator Arx (Aristaless related homeobox), a gene required for neocortical development, and NCAM, encoding a cell adhesion molecule, among others lead to disrupted RMS migration and reduced olfactory bulb size 22,55 . This may be a result of failure of adult-generated SVZa neurons to deposit within the OB, or may reflect an earlier requirement for these genes on development.…”

“…These newly generated neurons are derived from SVZa glial fibrillary acidic protein (GFAP)-positive astrocytes 13,14 , which also ensheath them as they move through extensive interconnected networks along the lining of the lateral ventricle in the rostral forebrain and the rostral migratory stream (RMS) 15 . There, they are under the control of extracellular migration guidance cues, including the secreted ligands Slit and Reelin [16][17][18][19] , the receptors ErbB4 and Deleted in Colorectal Carcinoma (DCC) 20,21 , as well as integrins and neural cell adhesion molecule [21][22][23] . Upon reaching the bulb, the neurons turn and migrate in a radial direction 24 , integrating into either the granule cell layer or the periglomerular network 25 .…”

The SH2 domain-containing 5-phosphatase SHIP2 is expressed in the germinal layers of embryo and adult mouse brain: increased expression in N-CAM-deficient mice

“…1 and 2). Mice de¢cient for all splice variants (Cremer et al, 1994;Chazal et al, 2000) or only the 180-kDa isoform (Tomasiewicz et al, 1993) of N-CAM show an accumulation of migrating precursors from SVZ along the rostral migratory stream leading to a reduction in olfactory bulb size and granule cell density. In order to con¢rm the speci¢city of the SHIP2 expression observed in cells in the SVZa and in the rostral migratory stream and to address the putative e¡ect of N-CAM de¢ciency on SHIP2 level of expression, we examined the expression of SHIP2 mRNA in the adult brain of N-CAM knockout mice.…”