Structure Transcripts and Alternative Splicing of the Tau Gene

Microtubules are versatile polymers whose primary function is to generate specific cell morphologies and organize intracellular components. Microtubule-associated proteins (MAPs) are a disparate group of proteins that regulate the microtubule polymer state and also interact with other cytoskeletal and subcellular components (reviewed by Ramirez et al. 1999).

Tau is a microtubule-associated protein enriched in axons of mature and growing neurons (Kempf et al. 1996). Tau is also found in the cell nucleus associated with the nucleolus (Thurston et al. 1997), in the distal ends of growing neurons (Black et al. 1996; DiTella et al. 1994), in oligodendrocytes (Gorath et al. 2001), and in muscle (Wei and Andreadis 1998). Tau fulfills several functions, which include neurite extension, establishment of neuronal polarity, axonal microtubule assembly, stabilization and spacing, and interaction with the plasma membrane, possibly as part of signal transduction pathways (reviewed by Shahani and Brandt 2002). Tau undergoes extensive phosphorylation on Ser/Thr and Tyr residues in vivo (reviewed by Stoothoff and Johnson 2005). Phosphorylation affects the conformation and increases rigidity of the tau molecule, decreasing its affinity for microtubules.

Hyperphosphorylated, MT-dissociated tau protein is the major component of intracellular neurofibrillary tangles (NFTs), a hallmark of almost all types of neurodegeneration including Alzheimer's disease and the adult dementia that accompanies Down syndrome (Billingsley and Kincaid 1997; Lovestone and Reynolds 1997). NFTs, in the absence of extracellular amyloid deposits, define several neurodegenerative diseases grouped under the term "tangle-only tauopathies" (Ingram and Spillantini 2002; Sergeant et al. 2005). Among them are progressive supranuclear palsy (PSP), corti-cobasal degeneration (CBD), Pick's disease (PiD), argyrophilic grain disease, and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Hyperphosphorylated tau is also found in patients suffering from myopathies: NFTs form in the brains of sufferers from myotonic dystrophy type 1 (DM 1), a pleiotropic disorder whose symptoms include dementia (Modoni et al. 2004; Sergeant et al. 2001) and NFT-like aggregates are present in the muscles of people suffering from inclusion-body myositis (reviewed by Askanas and Engel 2002).

Tau is encoded by a single-copy gene located on chromosome 17q21.1 in humans (Himmler 1989; Neve et al. 1986). It produces three transcripts of 2, 6, and 9 kb which are differentially expressed in the nervous system, depending upon stage of neuronal maturation and neuron type (reviewed in Andreadis 2005). Figure 1A shows the exon structure and splicing patterns of the tau gene and Fig. 1B shows the effects of splicing decisions on the molecule's function. Eight of the sixteen tau exons (2, 3, 4A, 6, 8, 10, 13, 14) are alternatively spliced (reviewed in Andreadis 2005). The resulting protein isoforms are a series of closely spaced bands from 58 kD to 66 kD and, in some neuronal tissues, a 110 kD isoform arising from the 9 kb mRNA (Drubin et al. 1988; Oblinger et al. 1991).

Figure 1C shows the tau isoforms that are prevalent in brain. Their relative abundance is spatially and temporally regulated: Exons 2, 3, and 10 are adult-specific, but their ratios differ in various CNS compartments. The exact function and ligands of exons 2 and 3 are unknown, although the N-terminal domain of tau interacts with the plasma membrane (Brandt et al. 1995) and undergoes phosphorylation by fyn at residue Tyr18 (Lee et al. 2004). Exon 10 increases tau affinity for microtubules, by introducing an additional "repeat" sequence of 31 amino acids (cassette exon 10) into the microtubule-binding domain of tau (the other microtubule-binding repeats are in exons 9, 11, and 12; Himmler et al. 1989; Lee et al. 1989).

All six possible product combinations of the 2/3/10 splicing events have been observed (Goedert et al 1989a; Himmler 1989; Kosik et al 1989),

Fig. 1A-C. Tau mRNA species and the functions of the ensuing domains. A: Schematic representation of exons and splicing pathways in the tau gene. Black = constitutive; white = regulated (A = adult-specific, PNS = specific to the peripheral nervous system, C = complex, ? = unknown); horizontal stripes = transcribed, untranslated regions; vertical stripes = alternative/additional reading frames. An indicate polyadenylation sites. The numbers underneath the exons indicate possible outcomes from each alternatively spliced region within the tau transcript. B: Diagram of the longest tau isoform. Above the diagram the general nature of the domain is noted. Below the diagram is a list of domain functions and of diseases in which the splicing of that particular region is or may be altered. C: Schematic depictions of tau isoforms abundant in the CNS. On the left is the length of each isoform in amino acids, on the right its relative abundance in adult CNS. Below the diagrams is a scale bar (aa = amino acids) and the drawing conventions for exons 2, 3, and 10

Fig. 1A-C. Tau mRNA species and the functions of the ensuing domains. A: Schematic representation of exons and splicing pathways in the tau gene. Black = constitutive; white = regulated (A = adult-specific, PNS = specific to the peripheral nervous system, C = complex, ? = unknown); horizontal stripes = transcribed, untranslated regions; vertical stripes = alternative/additional reading frames. An indicate polyadenylation sites. The numbers underneath the exons indicate possible outcomes from each alternatively spliced region within the tau transcript. B: Diagram of the longest tau isoform. Above the diagram the general nature of the domain is noted. Below the diagram is a list of domain functions and of diseases in which the splicing of that particular region is or may be altered. C: Schematic depictions of tau isoforms abundant in the CNS. On the left is the length of each isoform in amino acids, on the right its relative abundance in adult CNS. Below the diagrams is a scale bar (aa = amino acids) and the drawing conventions for exons 2, 3, and 10

indicating that separate factors govern their splicing - a conclusion confirmed by extensive studies of splicing-factor effects on these exons (Arikan et al. 2002; Gao et al. 2000; Li et al. 2003; Wang et al. 2004; Wang et al. 2005). The expression pattern of exon 10 shows a crucial difference between rodent and human, which becomes relevant in neurodegeneration: exon 10 becomes constitutive in adult rodents (Kosik et al. 1989) whereas it remains regulated in the CNS of adult humans (Gao et al. 2000; Goedert et al. 1989b).

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