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Glutamate Transporter Mrna Expression in Proliferative Zones of the Developing and Adult Murine CNS

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Glutamate Transporter Mrna Expression in Proliferative Zones of the Developing and Adult Murine CNS The Journal of Neuroscience, April 1, 1996, 76(7):2191-2207 Glutamate Transporter mRNA Expression in Proliferative Zones of the Developing and Adult Murine CNS Margaret L. Sutherland,is2 Tracy A. Delaney,’ and Jeffrey L. Noebels’s2 1Division of Neuroscience, “Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, Houston, Texas 77030 Neuronal migration, differentiation, and synapse formation are transcript expression continued in the subventricular zone developmental processes within the CNS significantly influ- postnatally and persisted in this proliferative zone in the adult enced by ionotropic and metabotropic glutamate receptor ac- brain. From PO onward, mEAAT1 mRNA was present predom- tivity. Extracellular glutamate concentrations mediating this ac- inantly in the cerebellar Purkinje cell layer and at a much lower tivity are regulated by transport proteins localized in neuronal abundance in the cortex, hippocampus, basal nuclei, and sep- and glial cell membranes. We have used in situ hybridization tum, whereas from P7 onward, mEAAT2 mRNA expression analysis with subtype-specific antisense-oligonucleotides to increased throughout most of the neuraxis. Postnatally, tran- study the distribution of glia-specific excitatory amino acid scripts for mEAAT1 and mEAAT2 were found in cell bodies, transporter (mEAAT1 and mEAAT2) mRNAs during the later processes, and commissural white matter tracts of the CNS. stages of embryogenesis and postnatal CNS development. The divergent temporal and spatial expression of EAAT sub- Distinct but overlapping embryonic and postnatal patterns of types and their persistence in mature fiber tracts and radial glia localization were observed for the two transporter transcripts. layers reveal that specific EAATs are likely to play multiple Both mEAAT1 and mEAAT2 mRNAs were found during the distinct roles in the developing and adult CNS, including the peak period of gliogenesis (E15E19) in the telencephalic and regulation of cell proliferation, axon-glia interactions, and neu- mesencephalic CNS proliferative zones. The overall expression ronal survival. of mEAAT1 mRNA diminished after the completion of cell mi- Key words: excitatory amino acid transporters; development; gration, whereas mEAAT2 mRNA expression increased signif- in situ hybridization; proliferative zones; CNS; temporal and icantly during postnatal development. Interestingly, mEAAT2 spatial expression Glutamate, the principle excitatory amino acid neurotransmitter the maintenance of extracellular levels of glutamate below neu- of the mammalian CNS, is a signal for a number of diverse rotoxic concentrations (Nicholls and Attwell, 1990; Kanai et al., developmental events, including cell migration and differentiation 1993). Alteration of ion gradients can cause a reversal of excita- (Pearce et al., 1987; Mattson et al., 1988; Komuro and Rakic, tory amino acid transporter (EAAT) function (Attwell et al., 1993) activation of second-messenger cascades involved in the 1993) resulting in elevated extracellular glutamate levels and modulation of neuronal and astrocytic proliferation (Nicoletti et excitotoxic cell death (Choi et al., 1987; Ikeda et al., 1989; Szat- al., 1990; LoTurco and Kriegstein, 1991) regulation of early gene kowski et al., 1990; Bouvier et al., 1992; Mad1 and Burgesser, expression (Arenander et al., 1989), cell death (Oka et al., 1993) 1993). and participation in the construction, refinement, and mainte- A gene family that mediates the cellular uptake of acidic and nance of synaptic circuitry (Mattson et al., 1988; McDonald and neutral amino acids in vertebrates has been identified by cDNA Johnston, 1990). The extracellular level of glutamate, as well as isolation (for reviews, see Kanai et al., 1993; Kanner, 1993; Amara fast transmission at some glutamatergic synapses (Mcnncrick and and Arriza, 19Y3). Four distinct subtypes of EAATs (Kanai and Zorumski, 1994; Takahashi ct al., 1995) is rcgulatcd by diffusion Hcdigcr, lYY2; Pines et al., lYY2; Storck et al., 1992; Shashidharan and active rcuptake of ncurotransmitter into presynaptic termi- and Plaitakis, 1993; Tanaka, 1993a,b; Arriza et al., 1994; nals and surrounding glial cells by membrane-localized transport Kawakami ct al., 1994; Kirschner ct al., lYY4; Shashidharan et al., proteins (for review, see Amara and Arriza, lYY3). 1994; Fairman et al., 19Y.5; Sutherland ct al., lYY5) have been Uptake is an electrogenic process that moves glutamate and dcfincd by diffcrenccs in sequence, pharmacology, tissue distribu- Naf ions into the cell, while countcrtransporting Km’ and OH or tion, and channel-like properties. EAATl, EAAT2, and EAAT3 HCO, ions outward (Bouvier et al., 1992; Attwell and Mobbs, share a >50% amino acid identity among subtypes and a >90% 1994). The quantity of charge translocated with glutamate is amino acid identity across species. Recent immunocytochemical voltage- and subtype-dependent (Wadiche et al., 1995a,b). In the analysis of EAAT subtypes has identified EAATl and EAAT2 adult brain, an essential role of excitatory amino acid transport is (Rothstein et al., 1994; Lehre et al., 1995) proteins in the cell bodies and processes of astroglia and the EAAT3 protein in Rcceivcd Nov. 28, 1995; revised Jan. 18, 1996; acccptcd Jan. 23, 1996. This work was supported by National Tnstitutcs of Flealth Grants NS297OY and neuronal cell bodies, axons, presynaptic terminals, and dendrites NSll535. M.L.S. is the recipient of an American Epilepsy Society Postdoctoral (Rothstein et al., 1994). Fellowship. WC thank Alex Kogan for photographic assistance. The existence of multiple EAAT subtypes raises the possibility Corrcapondencc should he addressed to Dr. Margaret Sutherland, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. that EAATs may play a variety of roles in the developing and Copyright 0 1996 Society for Neurowience 0270-h474/9h/l62191-17$05.00/O adult CNS. These predicted roles depend in part on the temporal 2192 J. Neurosci., April 1, 1996, 76(7):2191-2207 Sutherland et al. l Developmental Expression of Murine Glutamate Transporter mRNAs 1 rEAAT1 1 MtksngeeprmGgrmerlQqgVRkrtllakkkvqsltkedvksylfrNafvLL--TVtaVIvGvc -T2 1 Maste-annmpk-ve--mhdshlsseePkhrnlgmrmcdKlgknl--Sl--fg--l-a nEZIAT3 1 MgkParkgcdskrflKn- wl--Stv-av-1 -iv 2 . - rEAAT1 64 tIlgfalrpykmSyreVkYFsFPGElLMRMLqMLvLPLIISSLvLPLIISSLvTG~LDSKaSG~G~WY mEAAT2 59 vcGrL1RlaSpihpdv-mlia---dI-----K--I--------I--lsg--a-V--rl-t--m-- nEAAT3 34 -GvLvReySnl-tldkf--a----I---KlvI--KlvI----v--mI--v-----nV---i-l---l- 3 rEAAT1 130 YMtTTIIAWiGIIiViiIHPGkgtKenmyreGK ivqVtaaDAFLDLIRNMFPpNLVeACFkQf mEAAT2 125 --s-----a-L-v-L-la----npklkkqlgp--knde-Ssl---------l--E---Q---Q-i nEAAT3 99 -fc--- ---iL--vL-vs-k--vtq-vdeidrtgstpe-Stv--m---------E---Q---Q-y 4 rEAAT1 196 KTsyeKRsfkvPiqsneTllgavinnvseamEtltrireEmvpVpgs~GvNaLGLv~smcFGf mEAAT2 186 q-vtk-vlvap-Seean-tkaviSmlnetmn-apEetkivikkglefkD-m-v---ig-fia--i nEAAT3 160 -- t-eevtaSddtgk~eeSvtavmttavsEnrtk-yrv-glysD-i-v---i--clv--l - 5 rEAAT1 262 VIGnMkEQGQaLrEFFdsLNEAiMrLVavI~aPLGILFLIAGKIvEmEDmgVIggQLa~tVT mEAAT2 252 am-K-G--aklmV---Ni---iv-K-- im----s----ac--c---Iaik-le-var--G--Mi- nEAAT3 223 ---K-G-k--i-Vd--I\TaLsd-t-Ki-qi--c-m------------I-v-- we-frk-Gl-M-- 6 7 0 rEAAT1 328 VIVGLlIHavIvLPLlYFlVTRKNPwvFigGllQALITALGTSSSSATLPiTIFkCLEENNGVDKR UT2 318 -----i--gg-f---I --v------Fs-fa-if-- w------a--ag---V--R---d-l-i--- nEAAT3 288 -Is--a--sivi---I --i-v----Fr-am-mt---l---mi--------V--R-a--k-r---- 8 9 rEAAT1 394 ITRFVLPVGATINMDGTALYEAlAAIFIAQvNnfDLnfDLnfGQIITISiTAT~SIG~GIPQAGLVT mEAAT2 384 v---------------------v-------m-gvi-dg---v-v-l---l------s--s----- nEAAT3 354 ----------------------V--v--si--l-~--si-------v-----------v------- rEAAT1 460 MVIVLTsVGLPTdDITLIIAWWfLDRlRTttNVLGDSlGAGIVEHLSrhEL knrDV mEAAT2 450 -lli--A-----E --s-lv----l---m--sV--v---F-----y---Ks--dtidsqhrmQe-i nEAAT3 420 -----sA----aE-v------------f--vV--vV-----aF-t----k--Kk-- eQm-- -m-----m-m-m. rEAAT1 518 EM -mm 2s m---m--mm-.vieeNE mKKpYqliaqdnepekpvADseTkm mlZAAT2 516 --tktqsiyddknhres-- nqcvyaahnswideckvtlaangks--csveeepwkree nEAAT3 478 ssevnivnpfalesatld--dsdt-- s-inggfavdksdtisftq-sqf Figure 1. Amino acid alignment of EAAT (l-3) subtypes. Identity between sequences is shown by a dash. Amino acids common to all three transporter proteins are indicated by bold lettering in the rEAAT1 sequence. Putative transmembrane domains, as determined by Kyte and Doolittle (1982) hydrophobicity analysis, are indicated by solid lines and numbers (l-9) above the aligned sequences. Consensus sites for PKC (S/T-X-R/K) and PKA (R/K-X-X-S/T) phosphorylation, which are common to all sequences, are shown above the alignment. Putative sites for N-linked glycosylation (N-X-S/T) are underlined. The amino acid positions of probes used for in situ histochemistry are indicated by dashed lines above the sequences. rEAAT1, (rat); mEAAT2, (mouse); nEAAT3, (rabbit). Amino acid identity (41-50%) is observed among EAAT subtypes. onset and cellular localization of EAAT subtype mRNA expres- nicked translated transcript-specific probe. Washes were performed at sion. Therefore we have used in situ hybridization analysis to 65°C in 0.1 X SSC (0.015 M NaCI, 0.0015 M Na, citrate, pH 7.6). determine the distribution of the two glial-type mouse glutamate Seclion preparution. Embryos and postnatal brains were ohtained by timed matings, with the appearance of a vaginal plug designated as transporter transcripts mEAAT1 and mEAAT2 during embryonic cmhryonic day 0.5 (E0.5) and the day
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