Hypomyelinating peripheral neuropathies and schwannomas in transgenic mice expressing SV40 T-antigen

Messing, Albee; Behringer, Richard R.; Wrabetz, Lawrence; Hammang, Joseph P.; Lemke, Greg; Palmiter, Richard D.; Brinster, Ralph L.

doi:10.1523/jneurosci.14-06-03533.1994

Cited by 26 publications

(21 citation statements)

References 21 publications

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“…The NF-Y control probe (major histocompatibility complex class II Y box sequence) bound a complex of the same mobility in Schwann cell extracts and was also supershifted by the NF-Y antibody (Fig. 7C, lanes [17][18][19][20]. Notably, this antibody did not alter the probe 4-specific doublet, C1 (lane 14) and did not supershift C1 on the probe containing site 4 alone (data not shown).…”

Section: Sequence Conservation and Promoter Deletion Analyses Reveal mentioning

confidence: 89%

“…Whereas C1 reflects the binding of an as yet unidentified protein, these results suggest that C2 contains transcription factor NF-Y in Schwann cell nuclear extracts. cells and are strongly up-regulated at the onset of peripheral myelination (19,20). Similarly, reporter genes linked to the same 5Ј-flanking region are transcribed at exceptionally high levels when transfected into Schwann cells but not when introduced into non-Schwann cells (18).…”

Section: Sequence Conservation and Promoter Deletion Analyses Reveal mentioning

confidence: 99%

“…Cell culture and transgenic mouse studies have demonstrated that major features of this regulation are controlled by a 1.1-kilobase pair region flanking the transcription start site of the P 0 gene. When linked to heterologous reporter genes, this 1.1-kilobase pair DNA fragment drives Schwann cell-specific, forskolin-inducible transcription upon transient transfection into cultured Schwann cells (18) and has been shown to target a number of transgenes exclusively to myelinating Schwann cells, on an appropriate developmental schedule, in transgenic mice (19,20). The 5Ј-DNA region therefore contains many if not most of the elements required for tissue-specific and developmentally accurate P 0 expression.…”

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confidence: 99%

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Multiple Regulatory Elements Control Transcription of the Peripheral Myelin Protein Zero Gene

Brown

Lemke

1997

Journal of Biological Chemistry

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The gene encoding protein zero (P 0 ), the most abundant protein of peripheral nervous system myelin, is expressed uniquely in Schwann cells. Previous studies have demonstrated that much of the cell type specificity of this expression is due to transcriptional control elements in the 1.1-kilobase pair 5-regulatory region of the gene. We have now analyzed this region and have identified a set of functional elements in the 500 base pairs proximal to the transcription start site. DNA sequence conservation within the 5 regions of the human, mouse, and rat P 0 genes correlates closely with the results of promoter deletion analysis of the 1.1-kilobase pair region assayed in Schwann cell cultures and reveals a potent proximal region from position ؊350 to ؉45. Sites of protein/DNA interaction within the proximal 500 base pairs of the promoter were identified by footprinting assays. Functional transcriptional elements were identified within the protected regions in the proximal promoter by mutation and transient transfection analysis in P 0 -expressing cell lines. The core (or basal) P 0 promoter is identified as two regulatory elements, a G/Crich element that binds nuclear factor Sp1 and a CAAT box that binds NF-Y. These core elements are essential for the transcription observed from the transfected promoter in cultured Schwann cells.The myelin sheath is a specialized membranous organelle of the vertebrate nervous system. Elaborated by oligodendrocytes in the central nervous system and by Schwann cells in the peripheral nervous system (PNS), 1 this organelle consists of a large sheet of plasma membrane that is repeatedly wrapped and very tightly compacted around axons (1). Myelin is essential for the rapid conduction of action potentials in vertebrates, and human diseases that compromise the integrity of the sheath (e.g. peripheral neuropathies in the PNS and multiple sclerosis in the central nervous system) are generally debilitating (2). The elaboration of myelin requires a substantial biosynthetic up-regulation of plasma membrane lipids and proteins, several of which are unique to the myelin sheath (3). In the PNS, the most abundant of these is protein zero (P 0 ), a 31-kilodalton, immunoglobulin-related, transmembrane glycoprotein that accounts for greater than 50% of the protein in mammalian PNS myelin (4). The mRNA encoding this protein is estimated to account for nearly 8% of the poly(A) RNA in actively myelinating Schwann cells (5).A variety of studies have demonstrated that P 0 is essential for peripheral nerve development and function. Mice in which the P 0 gene has been deleted exhibit a severe peripheral neuropathy that includes hypomyelination, loss of motor control, tremors, and grossly abnormal myelin sheaths (6, 7). Furthermore, mutations in the P 0 gene account for a variety of inherited human peripheral neuropathies, including Charcot-MarieTooth disease type 1B, Dejerine-Sottas syndrome, and congenital hypomyelination (8 -12).High level P 0 expression is a distinctive feature of terminal differentiatio...

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Section: Sequence Conservation and Promoter Deletion Analyses Reveal mentioning

confidence: 89%

Section: Sequence Conservation and Promoter Deletion Analyses Reveal mentioning

confidence: 99%

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confidence: 99%

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Multiple Regulatory Elements Control Transcription of the Peripheral Myelin Protein Zero Gene

Brown

Lemke

1997

Journal of Biological Chemistry

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“…Nf2 þ /À ;p53 þ /À cis mice (carrying the Nf2 and p53 mutation on the same chromosome 11) develop osteosarcomas and fibrosarcomas after a shorter latency period (5 months) than seen in either Nf2 þ /À or p53 þ /À mice. Loss of p53 may be important in tumorigenesis of P0-permissive murine cells in view of the observation that P0-SV40T antigen transgenic mice develop schwannomas (Messing et al, 1994).…”

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confidence: 99%

Synergy of Nf2 and p53 mutations in development of malignant tumours of neural crest origin

et al. 2004

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Previously, we have mimicked human neurofibromatosis type 2 (NF2) in conditional Nf2 mutant (P0Cre;Nf2 flox2/flox2 ) mice. Schwannomas, characteristic for NF2, were found at low frequency in older mice. Here, we report that these mice, upon additional hemizygosity for p53, rapidly develop multiple tumours showing features consistent with malignant peripheral nerve sheath tumours. Thus, p53 hemizygosity promotes tumorigenesis of mutant Nf2 peripheral nerve cells. In contrast, young P0Cre;Nf2 flox2/ þ ;p53 þ /À cis mice mainly succumb to Nf2/p53-related osteogenic tumours. Therefore, Cre-mediated early biallelic loss of Nf2 function in neural crest-derived cells hemizygous for p53 results in resistance to osteogenic tumours and increased susceptibility to peripheral nerve sheath tumours. Keywords: MPNST; neural crest; P0 promoter; conditional knockout mice; compensatory signalling Introduction Vestibular schwannomas are benign neural sheath tumours of the vestibular branch of the eighth cranial nerve. They occur either as bilateral tumours, the hallmark of the human hereditary cancer syndrome neurofibromatosis type 2 (NF2), or as sporadic unilateral tumours. Loss or mutational inactivation of both alleles of the NF2 gene in the Schwann cell is the ratelimiting step in neoplastic transformation. NF2 patients carrying one mutant NF2 allele are predisposed not only to bilateral vestibular schwannomas but also to schwannomas of other cranial, spinal and cutaneous nerves, to cranial and spinal meningiomas, as well as to presenile lens opacities and cerebral calcifications (McKusick, 1994). Loss of NF2 function is also frequently found in mesotheliomas (Bianchi et al., 1995). The product of the NF2 gene, called schwannomin or merlin (Rouleau et al., 1993;Trofatter et al., 1993), has structural similarity with members of the ezrin-radixin-moesin (ERM) family of proteins that link the cytoskeleton and the cell membrane (for a review, see, Bretscher et al., 2000). Together with ezrin and moesin, schwannomin and the transmembrane receptor CD44 form a molecular switch that specifies cell growth arrest or proliferation (Morrison et al., 2001).The role of loss of Nf2 function in development and tumorigenesis has been studied in various knockout mouse models. Embryos homozygous for Nf2 mutations causing either indirect skipping of exon 3 or 2-3 or direct deletion of exon 2 are lethal (McClatchey et al., 1998;Giovannini et al., 2000). They fail to initiate gastrulation between embryonic days 6.5 and 7.0 (McClatchey et al., 1997). Heterozygous Nf2 mutant mice do not mimic human NF2 but develop later in life (10-30 months) mainly osteomas and osteosarcomas showing loss of heterozygosity (LOH) for Nf2 (McClatchey et al., 1998;Giovannini et al., 2000). In addition, indications for a role of Nf2 loss in metastatic potential have been found (McClatchey et al., 1998). Previously, we have mimicked NF2 in conditonal Nf2 mutant mice with P0 promoter-directed Cre recombinase activity in Schwann cells (Giovannini et al., 2000). P0Cre;Nf2 fl...

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“…Using cultures of rat Schwann cells and transgenic mice, it was shown that a 1.1-kb promoter region of the rat P 0 promoter is sufficient to mediate Schwann cell-specific expression both in vitro and in vivo (27,29,30). Transient transfections have been used to analyze this region in further detail.…”

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confidence: 99%

Protein Zero Gene Expression Is Regulated by the Glial Transcription Factor Sox10

Peirano

Goerich

Riethmacher

et al. 2000

Molecular and Cellular Biology

209

220

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Myelinating glia express high levels of a unique set of genes which code for structural proteins of the myelin sheath. Few transcription factors have so far been implicated in the regulation of any myelin gene. Here we show that the protein zero (P 0 ) gene, a myelin gene exclusively expressed in the Schwann cell lineage of the peripheral nervous system, is controlled in its expression by the high-mobility-group domain protein Sox10 both in tissue culture and in vivo. Induction of wild-type Sox10, but not of other transcription factors or Sox10 mutants, strongly increased endogenous P 0 expression in tissue culture. This activation was mediated by the P 0 promoter, which was stimulated by Sox10 in transient transfections. Detailed analyses revealed the involvement of a proximal and a distal promoter region. The distal region functioned only in conjunction with the proximal one and contained a single Sox consensus binding site, which accounted for most of its activity. In contrast, the proximal region mediated Sox10 responsiveness on its own. It contained multiple binding sites for Sox proteins, with two high-affinity sites being the most significant. P 0 expression also depended on Sox10 in vivo, as evident from the analysis of Schwann cell precursors in mouse embryos with Sox10 mutation at day 12.5 of embryogenesis. To our knowledge this is the most conclusive link to date between a glial transcription factor and cell-specific activation of myelin gene expression.

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Hypomyelinating peripheral neuropathies and schwannomas in transgenic mice expressing SV40 T-antigen

Cited by 26 publications

References 21 publications

Multiple Regulatory Elements Control Transcription of the Peripheral Myelin Protein Zero Gene

Multiple Regulatory Elements Control Transcription of the Peripheral Myelin Protein Zero Gene

Synergy of Nf2 and p53 mutations in development of malignant tumours of neural crest origin

Protein Zero Gene Expression Is Regulated by the Glial Transcription Factor Sox10

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