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Cadherins in Brain Compartmentalisation 563 Juxtaposing the Transmembrane Domain of Pca-Cad6-HA Was Similarly Constructed

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Cadherins in Brain Compartmentalisation 563 Juxtaposing the Transmembrane Domain of Pca-Cad6-HA Was Similarly Constructed Development 128, 561-569 (2001) 561 Printed in Great Britain © The Company of Biologists Limited 2001 DEV1642 Role of cadherins in maintaining the compartment boundary between the cortex and striatum during development Takayoshi Inoue1,2, Taro Tanaka3, Masatoshi Takeichi3, Osamu Chisaka3, Shun Nakamura1 and Noriko Osumi4,* 1Division of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan 2Japan Science and Technology Corporation, 4-1-8, Hon-machi, Kawaguchi, Saitama 332-0012, Japan 3Department of Biophysics, Faculty of Science, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan 4Department of Developmental Neurobiology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan *Author for correspondence (e-mail: [email protected]) Accepted 29 November 2000; published on WWW 23 January 2001 SUMMARY In ventricular cells of the mouse telencephalon, differential trend for ectopic R-cadherin-expressing striatal cells. expression of cadherin cell adhesion molecules defines Although cadherin-6 gene knockout mice engineered in neighbouring regions; R-cadherin delineates the future this study showed no obvious phenotype in telencephalic cerebral cortex, while cadherin-6 delineates the lateral compartmentalisation, the preferential sorting of ectopic ganglionic eminence. By using cell labelling analyses in the cadherin-6-expressing cells was abolished in this mutant whole embryo culture system, we demonstrated that the background. Thus, the differential expression pattern of interface between R-cadherin and cadherin-6 expression is cadherins in the embryonic telencephalon is responsible for a boundary for cell lineage restriction at embryonic day maintaining the cortico-striatal compartment boundary. 10.5. Interestingly, when a group of cells with exogenous cadherin-6 were generated to straddle the cortico-straital boundary by electroporation at embryonic day 11.0, Key words: Cadherins, Cell lineage restriction, Compartment, ectopic cadherin-6-expressing cortical cells were sorted Electroporation, Mammalian whole embryo culture, Neuromeres, into the striatal compartment, and the reverse was the Telencephalon, Cortico-striatal boundary, Mouse INTRODUCTION compartmentalisation have been the major subject of early studies. For instance, expression of several transcription factors Compartmentalisation is one of the conserved morphogenetic or secretary molecules is known to delineate unique sets of strategies of multicellular organisms to pattern and maintain neuromeres (for reviews, see Puelles and Rubenstein, 1993; their body structures (for review, see Dahmann and Basler, Rubenstein et al., 1994; Lumsden and Krumlauf, 1996), 1999). In the development of the vertebrate central nervous suggesting differential chemoaffinities between compartment system, for example, the neural plate/tube is gradually units. Eph receptor tyrosine kinases and their ligands are subdivided into several longitudinal units called ‘neuromeres’ expressed in odd- and even-numbered rhombomeres in the (or ‘rhombomeres’, specifically for hindbrain subdivisions). zebrafish embryo (Xu et al., 1999), and bi-directional The results of several studies have clearly indicated that signalling at the rhombomere boundaries has been movement of neuroepithelial cells during development is demonstrated to inhibit intermixing of neuroepithelial cells confined within some of these units (Fraser et al., 1990; Figdor (Mellizer et al., 1999), thereby playing a crucial role in and Stern, 1993; Fishell et al., 1993). Such cell lineage compartmentalisation of the hindbrain (for review, see restricted compartment units must be significant in maintaining Lumsden, 1999). Another category of cell surface molecules, embryonic brain organisation since boundaries prevent cell adhesion molecules, have also been suggested to sort or cells, once patterned, from random intermingling during maintain cells within a compartment unit and/or at the border development. Neuromeres may also provide a basic framework regions through differential cellular affinities (Garcia-Bellido, for complex neuronal circuits as the neuromere boundaries 1966; Götz et al., 1996; Wizenmann and Lumsden, 1997), often match the territories between functional brain although the evidence is still indirect. subdivisions and with initial axonal tracts (Lumsden, 1990; Classic types of cadherin cell adhesion molecules are Figdor and Stern, 1993). grouped into more than 20 subclasses, each of which endows The molecular mechanisms underlying brain cells with selective adhesiveness; cells expressing particular 562 T. Inoue and others cadherin(s) prefer to bind those expressing similar cadherin(s) buffer (10 mM sodium citrate, pH 6.0) prior to fixation is necessary in a Ca2+-dependent manner (Nose et al., 1988; for reviews, to obtain intense signals with these antibodies. see Takeichi, 1991, 1995). Provided compartment units are differentially defined by cadherin expression, their Whole embryo culture and cell labelling method characteristic binding specificity could prevent cells from The experimental protocol was approved by the Ethics Review random intermixing. In support of this scenario, combinatorial Committee for Animal Experimentation of National Institute of Neuroscience. ICR mice were mated to obtain the embryos and the expression patterns of the cadherin subclasses is known to day of appearance of the vaginal plug was taken as E0. The protocols subdivide the embryonic brain into functional regions (for used for whole embryo culture (WEC) and neuroepithelial cell reviews, see Redies and Takeichi, 1996; Redies, 2000). For labelling have been described in detail previously (Osumi-Yamashita example, we have shown that cadherin-6 (cad6, Cdh6) and et al., 1997; Inoue et al., 2000). Briefly, DiI (Molecular Probes, D- R-cadherin (Rcad, Cdh4) delineate neighbouring brain 282) or DiO (Molecular Probes, D-275) was dissolved to saturation subdivisions, the lateral ganglionic eminence (lge) and the in dimethylformamide and stored at 4°C. For labelling of the future cerebral cortex (ctx), respectively, in ventricular cells of telencephalic neuroepithelium, an embryo ready for culture was held the embryonic day (E) 12.5 mouse telencephalon (Matsunami with a pair of tweezers and microinjected manually with a 10-fold and Takeichi, 1995; Inoue et al., 1997). Notably, dissociated diluted dye stock solution (Fig. 2A), yielding 10-50 labelled cells. cells from the ctx and lge of E14 rat embryos (roughly Each labelled spot was imaged under a binocular microscope (Leica, 2+ MZ 8) equipped with the CCD camera (Leica, 3CCD high gain colour corresponding to E12 mouse embryos) segregate in a Ca - camera), and the image was recorded by a colour video copy processor dependent manner in suspension cultures (Götz et al., 1996). (Mitsubishi, SCT-CP7000; Fig. 2B-E). Each embryo was then In addition, the ctx and lge are defined as cell lineage-restricted cultured in a separate glass bottle. After culture, the number of somites compartments, based on studies using slice preparations from and morphology of the embryos were carefully checked, and those E15 mouse embryos (Fishell et al., 1993). Rcad, the expression embryos exhibiting abnormal development were excluded from the of which is Pax6-dependent in the ctx, is also considered as a study. In our culture system, >90% of embryos at E10.5 developed candidate molecule for such selective affinity between the ctx normally for 24 hours, and >75% for 48 hours. The harvested embryos and lge (Stoykova et al., 1997). In the Xenopus neural tube, F- were fixed with 4% paraformaldehyde (PFA) in phosphate-buffered cadherin has already been shown to function in positioning of saline (PBS) for 12 hours at 4°C. The brain of each embryo was neuroepithelial cells at the sulcus limitans (Espeseth et al., dissected and cut sagittally in half. Photographs were taken using a fluorescent microscope (MZ FLIII, Leica) fitted with a filter suitable 1998). for DiI or DiO. Based on these early studies, we investigated whether more than one cadherin subclass, cad6 and Rcad, play important Establishment of cad6 mutant mice roles in formation/maintenance of the cortico-striatal To generate cad6 gene targeting mice, embryonic stem cells were (ctx/lge) boundary in the mouse embryo. We first confirmed transfected with the targeting construct (see Fig. 3A) using the method that the expression of Rcad and cad6 commences in the ctx described by Swiatek and Grindley (1993). Targeted embryonic stem and lge of the mouse telencephalon by E10.5. Then we found cells were genotyped by Southern blotting (Fig. 3B). Both embryos that restriction of ctx and lge cell mixing occurred in cultured and adult animals were genotyped by PCR (Fig. 3C). To detect the 185 bp band indicative of a wild-type allele, we employed primers embryos at E10.5. We next established cad6 gene knockout ′ mice, whose ctx/lge boundary was found to be corresponding to the first exon of cad6 gene, 6-44 (5 -AGCCCTA- CCCAACTTTCT-3′) and 6-228r18 (5′-CTTGCCCACGTACTGATA- morphologically normal and had normal cell lineage 3′). To detect the 680 bp band indicative of the mutant allele, primers restrictions, mainly because of redundant cadherins in the corresponding to the neomycin phosphotransferase gene, Neo3347 embryonic telencephalon. However, when various cadherin (5′-CCTGCTTGCCGAATATCA-3′) and 6-44. For western blotting
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