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Localized expression of the seizure-related gene SEZ-6 in developing and adult forebrains
Mechanisms of Development 118 (2002) 171–174 www.elsevier.com/locate/modo
Gene expression pattern
Localized expression of the seizure-related gene SEZ-6 in developing and adult forebrains Mary H. Kim, Jenny M. Gunnersen, Seong-Seng Tan* Brain Development Laboratory, Howard Florey Institute, The University of Melbourne, Parkville, Vic. 3010, Australia Received 19 April 2002; received in revised form 24 June 2002; accepted 25 June 2002
Abstract Despite its initial identification in neurons exposed to the seizure-inducing drug pentylentetrazole (PTZ), the function of the seizure-related gene SEZ-6 remains obscure. Expression analysis indicates specific expression in the adult brain and testis, and the structure of the predicted protein suggests putative roles in cell–cell recognition and signalling. We report here that type I SEZ-6 mRNA is strongly expressed in highly specific regions in the developing forebrain. Specifically, the pattern of SEZ-6 expression is closely tied with the emergence of the neocortical layers and hippocampus, and implies a forebrain-specific role for this gene during development. In the adult hippocampus, SEZ-6 appears to be a CA1-specific regional marker. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: SEZ-6; Seizure related; Neocortex; Thalamic eminence; Serial analysis of gene expression
1. Results and discussion SEZ-6 was first identified as a seizure-related gene following differential screening of mRNA from cortical neurons that were treated with pentylentetrazole (PTZ), a drug known to induce epileptic seizures (Shimizu-Nishikawa et al., 1995a). However, despite its mode of discovery, SEZ-6 has so far not been linked to an epilepsy-susceptibility loci or for that matter, to a PTZ-susceptibility loci (Wakana et al., 2000). Nor has SEZ-6 been shown to be capable of inducing bursting activity, a characteristic physiological attribute of neurons undergoing epileptic discharges, and a key sequelae of PTZ exposure. Despite these negative associations, the specific expression of SEZ-6 in key regions of the adult brain suggests important although yet unknown functions. Interestingly, the expression pattern of this gene during brain development is not known. The predicted primary structure of the SEZ-6 protein provides some insights into its putative function. Type I and type II isoforms of SEZ-6 appear to be transmembrane proteins with long extracellular domains and short C-terminal cytoplasmic domains whilst the type III isoform appears to be a secreted protein (Shimizu-Nishikawa et al., 1995b). The extracellular portion of the type I and type II isoforms possess five cysteine-rich motifs that are homologous to the short consensus repeats (SCR) found in the complement * Corresponding author. Tel.: 161-3-8344-7336; fax: 161-3-9348-1707. E-mail address: [email protected] (S.-S. Tan).
receptor C3b/C4b (Klickstein et al., 1987). In addition, there are two domains similar to the N-terminal half of the CUB domain, a motif found in signalling proteins including BMP-1 and Tolloid. Both SCR and CUB protein motifs are known to be involved in signalling and cell–cell adhesion or recognition. Finally, the cytoplasmic domain contains a potential target for tyrosine phosphorylation by members of Src tyrosine kinases (Herbst and Nicklin, 1997). Northern blots have indicated SEZ-6 mRNA in the adult brain and testis (Herbst and Nicklin, 1997). In the adult rat brain, SEZ-6 mRNA expression has been noted in the hippocampus, olfactory tubule, and certain sublayers of the neocortex (Herbst and Nicklin, 1997). In this report, we describe the highly restricted and stage-specific expression of SEZ-6 mRNA (type I isoform) in the developing forebrain. The onset of SEZ-6 expression at embryonic day (E) 11.5, coupled to its disappearance in the adult, suggest a developmental role for SEZ-6 during neocortical, hippocampal and thalamic development. SEZ-6 type I isoform was identified in our laboratory as a gene differentially expressed in the developing neocortex (Gunnersen et al., 2002). The SAGE (serial analysis of gene expression) technique compares the abundance of 10 bp sequence tags (downstream of the most 3 0 CATG restriction enzyme site) taken from every sampled transcript, hence identifying differentially-expressed genes (Velculescu et al., 1995). A comparison of 20 000 SAGE tags from E15.5 mouse neocortex with a comparable pool of
0925-4773/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0925-477 3(02)00238-1
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Fig. 1. Northern blot analysis of SEZ-6 mRNA expression in embryonic, postnatal and adult mouse neocortex. A 4 kb SEZ-6 transcript is detectable from E13.5 to P7 with hardly any expression at E11.5 or adult.
transcripts from post-natal day (P) 1 revealed the tag CCAGGAGAGG to be more highly expressed in the E15.5 library (10 tags) than at P1 (4 tags). The tag was mapped to Unigene cluster Mm. 4727 and identified as SEZ-6 using the Mus musculus Unigene ‘reliable’ tag-togene mapping dataset (www.ncbi.nlm.nih.gov/Unigene/). A cDNA clone (GenBank ID AW413142; corresponding to 3 0 end of the type 1 isoform) was used to generate probes for Northern blotting and in situ hybridization analyses. Northern blotting of neocortical tissue detected a 4 kb SEZ-6 transcript at embryonic and postnatal stages but not in the adult (Fig. 1). Hence, SEZ-6 expression correlates with the most active periods of cortical neurogenesis and neuronal maturation. However, expression could also be detected earlier (E11.5, Fig. 2A) in the preplate (PP), a subpial layer of cells which later splits to form the marginal zone and subplate. Preplate cells are the earliest postmitotic neurons in the developing neocortex and, even at this timepoint, corticofugal fibres are known to be emerging from PP cells (Molna´ r et al., 1998). At E13.5, the cerebral wall consists of a prominent ventricular zone (VZ) where progenitor cells are dividing to produce neuroblasts and secondary progenitors. SEZ-6 expression is absent from the VZ at all stages examined. Instead, SEZ-6 is found in the intermediate zone (IZ) where neurons are known to be migrating, and in the cortical plate (CP) where migrating neurons finally settle into defined cortical layers (Fig. 2B–H). At E13.5, SEZ-6 expression
extends from the medial limbic region around the cortical perimeter, terminating sharply at the piriform cortex (Fig. 2B,C, arrowheads). A coronal section through the anterior part of the E13.5 forebrain indicated very weak expression in the subpallial ganglionic eminence (GE) (Fig. 2B), but a more posterior section showed strong expression in the thalamic eminences (TE), transient structures that are found at the base of the dorsal thalamus and known to be rich in calretininstaining cells (Abbott and Jacobowitz, 1999) (Fig. 2C). Elsewhere in the forebrain, staining is either faint or absent. At E15.5, cortical neurogenesis is at its peak (Takahashi et al., 1996), and intense staining of SEZ-6 may be observed in the CP (Fig. 2D–F). Faint staining was observed in the IZ of the cerebral wall and in the subpallial GE (Fig. 2D,E). In addition, strong expression was found in the cortical hem of the developing hippocampus and the amygdala (Fig. 2F). Light staining may also be seen in the walls of the neural tube enclosing the third (V3) and fourth (V4) ventricles (Fig. 2F). The picture at E17.5 roughly mimics the situation at E15.5, except for the increased expression of SEZ-6 in the subventricular zone (SVZ) overlying the VZ in both neocortex and basal ganglia (Fig. 2G). A higher magnification shows strong expression in the CP and the underlying subplate (SP), a derivative of the PP (Fig. 2H). Following birth, SEZ-6 expression falls off rapidly in the neocortex except for faint staining in the mid-cortical layers (Fig. 2I). Staining persists in the cingulate cortex, and in the CA1 formation of the hippocampus whilst expression in the
Fig. 2. SEZ-6 expression in the mouse embryonic brain. At E11.5, SEZ-6 expression is localized to the preplate (A, arrow) and is absent from the ventricular zone (VZ) which is the most prominent layer during early cortical development. (B) At E13.5, expression is seen in the cortical plate (CP) across the entire periphery but terminates at the piriform cortex (B,C, arrowhead). SEZ-6 is also strongly expressed in the thalamic eminences (TE) (C). (D) An anterior coronal section at E15.5 displays expression along the CP and faint expression in the intermediate zone (IZ). (E) Higher magnification of inset in (D) shows strong SEZ-6 expression in the CP and weaker expression in the adjacent IZ and also the ganglionic eminence (GE). (F) A transverse section through the E15.5 mouse brain exhibits strong staining in the CP and weaker staining in the IZ, GE, thalamus and hindbrain. The expression in the medial limbic cortex extends to the cortical hem (H). (G) At E17.5, SEZ-6 expression appears similar to that observed at E15.5 except for clearer definition of staining in the thicker CP. (H) Higher power view of inset in (G) shows strong staining in the CP and weak staining in the SVZ and IZ. Strong staining may be seen in the subplate (SP). SEZ-6 expression in the mouse postnatal forebrain and cerebellum (I–K). (I) At P1, SEZ-6 is faintly expressed in the deep layers of the neocortex with stronger expression in the cingulate cortex and the CA1 field of the hippocampus, and weak staining in the dentate gyrus and CA3 field. (J) SEZ-6 expression is also observed in the Purkinje cell layer and the presumptive internal granular cell layer of the cerebellum. (K) In the adult, SEZ-6 expression is seen only in the CA1 field and no expression may be detected in the neocortex. Abbreviations: CA1, cornu ammonis 1; CA3, cornu ammonis 3; Cc, cingulate cortex; Cer, Cerebellum; cp, choroid plexus; CP, cortical plate; DG, dentate gyrus; DT, dorsal thalamus; GE, ganglionic eminence; H, cortical hem; HB, hindbrain; Hyp, hypothalamus; IZ, intermediate zone; LV, lateral ventricle; NCx, neocortex; PCL, Purkinje cell layer; PP, preplate; S, septum; SP, subplate; SVZ, subventricular zone (striatum); T, thalamus; TE, thalamic eminence; V3, third ventricle; V4, fourth ventricle; VZ, ventricular zone. Scale bars: A,E,H,J, 270 mm; B–D,F,G,K, 675 mm; I, 450 mm.
M.H. Kim et al. / Mechanisms of Development 118 (2002) 171–174
CA3 field and dentate gyrus (DG) is very faint or absent. In this respect, SEZ-6 may be an important genetic marker for the CA1 field in both postnatal and adult hippocampi (Fig. 2K). More posteriorly, in the cerebellum SEZ-6 expression may be found in both the Purkinje and presumptive internal granular cell layers at P1 (Fig. 2J).
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with T3 RNA polymerase and the digoxigenin label detected using anti-digoxigenin Fabs coupled to alkaline phosphatase and NBT/BCIP (Roche). Signals were not detected in the sense controls.
References 2. Experimental procedures C57/BL6 mice were used throughout the study. The morning of the vaginal plug was defined as embryonic day 0.5. For Northern blot analysis, total RNA was isolated from neocortical tissues dissected at various time points using standard protocols. In situ hybridization was carried out on 20-mm sections with antisense probes transcribed
Abbott, L.C., Jacobowitz, D.M., 1999. Developmental expression of calretinin-immunoreactivity in the thalamic eminence of the fetal mouse. Int. J. Dev. Neurosci. 17, 331–346. Gunnersen, J.M., Augustine, C., Spirkoska, V., Kim, M., Brown, M., Tan, S.-S., 2002. Global analysis of gene expression patterns in developing mouse neocortex using Serial Analysis of Gene Expression (SAGE). Mol. Cell. Neurosci. 19, 560–573. Herbst, R., Nicklin, M.J.H., 1997. SEZ6: promoter selectivity, genomic
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M.H. Kim et al. / Mechanisms of Development 118 (2002) 171–174
structure and localized expression in the brain. Mol. Brain Res. 44, 309– 322. Klickstein, L.B., Wong, W.W., Smith, J.A., Weis, J.H., Wilson, J.G., Fearon, D.T., 1987. Human C3b/C4b receptor (CR1). Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristics of C3/C4 binding proteins. J. Exp. Med. 165, 1095–1112. Molna´ r, Z., Adams, R., Blakemore, C., 1998. Mechanisms underlying the early establishment of thalamocortical connections in the rat. J. Neurosci. 18, 5723–5745. Shimizu-Nishikawa, K., Kajiwara, K., Sugaya, E., 1995a. Cloning and characterization of seizure-related gene, SEZ-6. Biochem. Biophys. Res. Commun. 216, 382–389.
Shimizu-Nishikawa, K., Kajiwara, K., Kimura, M., Katsuki, M., Sugaya, E., 1995b. Cloning and expression of SEZ-6, a brain-specific and seizure-related cDNA. Mol. Brain Res. 28, 201–210. Takahashi, T., Nowakowski, R.S., Caviness, V.C., 1996. The leaving or Q fraction of the murine cerebral proliferative epithelium: a general model of neocortical neuronogenesis. J. Neurosci. 16, 6183–6196. Velculescu, V.E., Zhang, L., Vogelstein, B., Kinzler, K.W., 1995. Serial analysis of gene expression. Science 270, 484–487. Wakana, S., Sugaya, E., Naramoto, F., Yokote, N., Maruyama, C., Jin, W., Ohguchi, H., Tsuda, T., Sugaya, A., Kajiwara, K., 2000. Gene mapping of SEZ group genes and determination of pentylenetetrazol susceptible quantitative trait loci in the mouse chromosome. Brain Res. 857, 286– 290.
Gene expression pattern
Localized expression of the seizure-related gene SEZ-6 in developing and adult forebrains Mary H. Kim, Jenny M. Gunnersen, Seong-Seng Tan* Brain Development Laboratory, Howard Florey Institute, The University of Melbourne, Parkville, Vic. 3010, Australia Received 19 April 2002; received in revised form 24 June 2002; accepted 25 June 2002
Abstract Despite its initial identification in neurons exposed to the seizure-inducing drug pentylentetrazole (PTZ), the function of the seizure-related gene SEZ-6 remains obscure. Expression analysis indicates specific expression in the adult brain and testis, and the structure of the predicted protein suggests putative roles in cell–cell recognition and signalling. We report here that type I SEZ-6 mRNA is strongly expressed in highly specific regions in the developing forebrain. Specifically, the pattern of SEZ-6 expression is closely tied with the emergence of the neocortical layers and hippocampus, and implies a forebrain-specific role for this gene during development. In the adult hippocampus, SEZ-6 appears to be a CA1-specific regional marker. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: SEZ-6; Seizure related; Neocortex; Thalamic eminence; Serial analysis of gene expression
1. Results and discussion SEZ-6 was first identified as a seizure-related gene following differential screening of mRNA from cortical neurons that were treated with pentylentetrazole (PTZ), a drug known to induce epileptic seizures (Shimizu-Nishikawa et al., 1995a). However, despite its mode of discovery, SEZ-6 has so far not been linked to an epilepsy-susceptibility loci or for that matter, to a PTZ-susceptibility loci (Wakana et al., 2000). Nor has SEZ-6 been shown to be capable of inducing bursting activity, a characteristic physiological attribute of neurons undergoing epileptic discharges, and a key sequelae of PTZ exposure. Despite these negative associations, the specific expression of SEZ-6 in key regions of the adult brain suggests important although yet unknown functions. Interestingly, the expression pattern of this gene during brain development is not known. The predicted primary structure of the SEZ-6 protein provides some insights into its putative function. Type I and type II isoforms of SEZ-6 appear to be transmembrane proteins with long extracellular domains and short C-terminal cytoplasmic domains whilst the type III isoform appears to be a secreted protein (Shimizu-Nishikawa et al., 1995b). The extracellular portion of the type I and type II isoforms possess five cysteine-rich motifs that are homologous to the short consensus repeats (SCR) found in the complement * Corresponding author. Tel.: 161-3-8344-7336; fax: 161-3-9348-1707. E-mail address: [email protected] (S.-S. Tan).
receptor C3b/C4b (Klickstein et al., 1987). In addition, there are two domains similar to the N-terminal half of the CUB domain, a motif found in signalling proteins including BMP-1 and Tolloid. Both SCR and CUB protein motifs are known to be involved in signalling and cell–cell adhesion or recognition. Finally, the cytoplasmic domain contains a potential target for tyrosine phosphorylation by members of Src tyrosine kinases (Herbst and Nicklin, 1997). Northern blots have indicated SEZ-6 mRNA in the adult brain and testis (Herbst and Nicklin, 1997). In the adult rat brain, SEZ-6 mRNA expression has been noted in the hippocampus, olfactory tubule, and certain sublayers of the neocortex (Herbst and Nicklin, 1997). In this report, we describe the highly restricted and stage-specific expression of SEZ-6 mRNA (type I isoform) in the developing forebrain. The onset of SEZ-6 expression at embryonic day (E) 11.5, coupled to its disappearance in the adult, suggest a developmental role for SEZ-6 during neocortical, hippocampal and thalamic development. SEZ-6 type I isoform was identified in our laboratory as a gene differentially expressed in the developing neocortex (Gunnersen et al., 2002). The SAGE (serial analysis of gene expression) technique compares the abundance of 10 bp sequence tags (downstream of the most 3 0 CATG restriction enzyme site) taken from every sampled transcript, hence identifying differentially-expressed genes (Velculescu et al., 1995). A comparison of 20 000 SAGE tags from E15.5 mouse neocortex with a comparable pool of
0925-4773/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0925-477 3(02)00238-1
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Fig. 1. Northern blot analysis of SEZ-6 mRNA expression in embryonic, postnatal and adult mouse neocortex. A 4 kb SEZ-6 transcript is detectable from E13.5 to P7 with hardly any expression at E11.5 or adult.
transcripts from post-natal day (P) 1 revealed the tag CCAGGAGAGG to be more highly expressed in the E15.5 library (10 tags) than at P1 (4 tags). The tag was mapped to Unigene cluster Mm. 4727 and identified as SEZ-6 using the Mus musculus Unigene ‘reliable’ tag-togene mapping dataset (www.ncbi.nlm.nih.gov/Unigene/). A cDNA clone (GenBank ID AW413142; corresponding to 3 0 end of the type 1 isoform) was used to generate probes for Northern blotting and in situ hybridization analyses. Northern blotting of neocortical tissue detected a 4 kb SEZ-6 transcript at embryonic and postnatal stages but not in the adult (Fig. 1). Hence, SEZ-6 expression correlates with the most active periods of cortical neurogenesis and neuronal maturation. However, expression could also be detected earlier (E11.5, Fig. 2A) in the preplate (PP), a subpial layer of cells which later splits to form the marginal zone and subplate. Preplate cells are the earliest postmitotic neurons in the developing neocortex and, even at this timepoint, corticofugal fibres are known to be emerging from PP cells (Molna´ r et al., 1998). At E13.5, the cerebral wall consists of a prominent ventricular zone (VZ) where progenitor cells are dividing to produce neuroblasts and secondary progenitors. SEZ-6 expression is absent from the VZ at all stages examined. Instead, SEZ-6 is found in the intermediate zone (IZ) where neurons are known to be migrating, and in the cortical plate (CP) where migrating neurons finally settle into defined cortical layers (Fig. 2B–H). At E13.5, SEZ-6 expression
extends from the medial limbic region around the cortical perimeter, terminating sharply at the piriform cortex (Fig. 2B,C, arrowheads). A coronal section through the anterior part of the E13.5 forebrain indicated very weak expression in the subpallial ganglionic eminence (GE) (Fig. 2B), but a more posterior section showed strong expression in the thalamic eminences (TE), transient structures that are found at the base of the dorsal thalamus and known to be rich in calretininstaining cells (Abbott and Jacobowitz, 1999) (Fig. 2C). Elsewhere in the forebrain, staining is either faint or absent. At E15.5, cortical neurogenesis is at its peak (Takahashi et al., 1996), and intense staining of SEZ-6 may be observed in the CP (Fig. 2D–F). Faint staining was observed in the IZ of the cerebral wall and in the subpallial GE (Fig. 2D,E). In addition, strong expression was found in the cortical hem of the developing hippocampus and the amygdala (Fig. 2F). Light staining may also be seen in the walls of the neural tube enclosing the third (V3) and fourth (V4) ventricles (Fig. 2F). The picture at E17.5 roughly mimics the situation at E15.5, except for the increased expression of SEZ-6 in the subventricular zone (SVZ) overlying the VZ in both neocortex and basal ganglia (Fig. 2G). A higher magnification shows strong expression in the CP and the underlying subplate (SP), a derivative of the PP (Fig. 2H). Following birth, SEZ-6 expression falls off rapidly in the neocortex except for faint staining in the mid-cortical layers (Fig. 2I). Staining persists in the cingulate cortex, and in the CA1 formation of the hippocampus whilst expression in the
Fig. 2. SEZ-6 expression in the mouse embryonic brain. At E11.5, SEZ-6 expression is localized to the preplate (A, arrow) and is absent from the ventricular zone (VZ) which is the most prominent layer during early cortical development. (B) At E13.5, expression is seen in the cortical plate (CP) across the entire periphery but terminates at the piriform cortex (B,C, arrowhead). SEZ-6 is also strongly expressed in the thalamic eminences (TE) (C). (D) An anterior coronal section at E15.5 displays expression along the CP and faint expression in the intermediate zone (IZ). (E) Higher magnification of inset in (D) shows strong SEZ-6 expression in the CP and weaker expression in the adjacent IZ and also the ganglionic eminence (GE). (F) A transverse section through the E15.5 mouse brain exhibits strong staining in the CP and weaker staining in the IZ, GE, thalamus and hindbrain. The expression in the medial limbic cortex extends to the cortical hem (H). (G) At E17.5, SEZ-6 expression appears similar to that observed at E15.5 except for clearer definition of staining in the thicker CP. (H) Higher power view of inset in (G) shows strong staining in the CP and weak staining in the SVZ and IZ. Strong staining may be seen in the subplate (SP). SEZ-6 expression in the mouse postnatal forebrain and cerebellum (I–K). (I) At P1, SEZ-6 is faintly expressed in the deep layers of the neocortex with stronger expression in the cingulate cortex and the CA1 field of the hippocampus, and weak staining in the dentate gyrus and CA3 field. (J) SEZ-6 expression is also observed in the Purkinje cell layer and the presumptive internal granular cell layer of the cerebellum. (K) In the adult, SEZ-6 expression is seen only in the CA1 field and no expression may be detected in the neocortex. Abbreviations: CA1, cornu ammonis 1; CA3, cornu ammonis 3; Cc, cingulate cortex; Cer, Cerebellum; cp, choroid plexus; CP, cortical plate; DG, dentate gyrus; DT, dorsal thalamus; GE, ganglionic eminence; H, cortical hem; HB, hindbrain; Hyp, hypothalamus; IZ, intermediate zone; LV, lateral ventricle; NCx, neocortex; PCL, Purkinje cell layer; PP, preplate; S, septum; SP, subplate; SVZ, subventricular zone (striatum); T, thalamus; TE, thalamic eminence; V3, third ventricle; V4, fourth ventricle; VZ, ventricular zone. Scale bars: A,E,H,J, 270 mm; B–D,F,G,K, 675 mm; I, 450 mm.
M.H. Kim et al. / Mechanisms of Development 118 (2002) 171–174
CA3 field and dentate gyrus (DG) is very faint or absent. In this respect, SEZ-6 may be an important genetic marker for the CA1 field in both postnatal and adult hippocampi (Fig. 2K). More posteriorly, in the cerebellum SEZ-6 expression may be found in both the Purkinje and presumptive internal granular cell layers at P1 (Fig. 2J).
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with T3 RNA polymerase and the digoxigenin label detected using anti-digoxigenin Fabs coupled to alkaline phosphatase and NBT/BCIP (Roche). Signals were not detected in the sense controls.
References 2. Experimental procedures C57/BL6 mice were used throughout the study. The morning of the vaginal plug was defined as embryonic day 0.5. For Northern blot analysis, total RNA was isolated from neocortical tissues dissected at various time points using standard protocols. In situ hybridization was carried out on 20-mm sections with antisense probes transcribed
Abbott, L.C., Jacobowitz, D.M., 1999. Developmental expression of calretinin-immunoreactivity in the thalamic eminence of the fetal mouse. Int. J. Dev. Neurosci. 17, 331–346. Gunnersen, J.M., Augustine, C., Spirkoska, V., Kim, M., Brown, M., Tan, S.-S., 2002. Global analysis of gene expression patterns in developing mouse neocortex using Serial Analysis of Gene Expression (SAGE). Mol. Cell. Neurosci. 19, 560–573. Herbst, R., Nicklin, M.J.H., 1997. SEZ6: promoter selectivity, genomic
174
M.H. Kim et al. / Mechanisms of Development 118 (2002) 171–174
structure and localized expression in the brain. Mol. Brain Res. 44, 309– 322. Klickstein, L.B., Wong, W.W., Smith, J.A., Weis, J.H., Wilson, J.G., Fearon, D.T., 1987. Human C3b/C4b receptor (CR1). Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristics of C3/C4 binding proteins. J. Exp. Med. 165, 1095–1112. Molna´ r, Z., Adams, R., Blakemore, C., 1998. Mechanisms underlying the early establishment of thalamocortical connections in the rat. J. Neurosci. 18, 5723–5745. Shimizu-Nishikawa, K., Kajiwara, K., Sugaya, E., 1995a. Cloning and characterization of seizure-related gene, SEZ-6. Biochem. Biophys. Res. Commun. 216, 382–389.
Shimizu-Nishikawa, K., Kajiwara, K., Kimura, M., Katsuki, M., Sugaya, E., 1995b. Cloning and expression of SEZ-6, a brain-specific and seizure-related cDNA. Mol. Brain Res. 28, 201–210. Takahashi, T., Nowakowski, R.S., Caviness, V.C., 1996. The leaving or Q fraction of the murine cerebral proliferative epithelium: a general model of neocortical neuronogenesis. J. Neurosci. 16, 6183–6196. Velculescu, V.E., Zhang, L., Vogelstein, B., Kinzler, K.W., 1995. Serial analysis of gene expression. Science 270, 484–487. Wakana, S., Sugaya, E., Naramoto, F., Yokote, N., Maruyama, C., Jin, W., Ohguchi, H., Tsuda, T., Sugaya, A., Kajiwara, K., 2000. Gene mapping of SEZ group genes and determination of pentylenetetrazol susceptible quantitative trait loci in the mouse chromosome. Brain Res. 857, 286– 290.