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Developmental expression and differentiation-related neuron-specific splicing of metastasis suppressor 1 (Mtss1) in normal and transformed cerebellar cells.

Glassmann A, Molly S, Surchev L, Nazwar TA, Holst M, Hartmann W, Baader SL, Oberdick J, Pietsch T, Schilling K - BMC Dev. Biol. (2007)

Bottom Line: In the adult CNS, Mtss1 is found exclusively in cerebellar Purkinje cells.Both the pattern of expression and splicing of Mtss1 is developmentally regulated in the murine cerebellum.These findings are discussed with a view on the potential role of Mtss1 for cytoskeletal dynamics in developing and mature cerebellar neurons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Anatomisches Institut, Anatomie & Zellbiologie, University of Bonn, Bonn, Germany. alexander.glassmann@uni-bonn.de

ABSTRACT

Background: Mtss1 encodes an actin-binding protein, dysregulated in a variety of tumors, that interacts with sonic hedgehog/Gli signaling in epidermal cells. Given the prime importance of this pathway for cerebellar development and tumorigenesis, we assessed expression of Mtss1 in the developing murine cerebellum and human medulloblastoma specimens.

Results: During development, Mtss1 is transiently expressed in granule cells, from the time point they cease to proliferate to their synaptic integration. It is also expressed by granule cell precursor-derived medulloblastomas. In the adult CNS, Mtss1 is found exclusively in cerebellar Purkinje cells. Neuronal differentiation is accompanied by a switch in Mtss1 splicing. Whereas immature granule cells express a Mtss1 variant observed also in peripheral tissues and comprising exon 12, this exon is replaced by a CNS-specific exon, 12a, in more mature granule cells and in adult Purkinje cells. Bioinformatic analysis of Mtss1 suggests that differential exon usage may affect interaction with Fyn and Src, two tyrosine kinases previously recognized as critical for cerebellar cell migration and histogenesis. Further, this approach led to the identification of two evolutionary conserved nuclear localization sequences. These overlap with the actin filament binding site of Mtss1, and one also harbors a potential PKA and PKC phosphorylation site.

Conclusion: Both the pattern of expression and splicing of Mtss1 is developmentally regulated in the murine cerebellum. These findings are discussed with a view on the potential role of Mtss1 for cytoskeletal dynamics in developing and mature cerebellar neurons.

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A: Sequence comparison of exon 12a of Mtss1 in various mammals. Sequence rendered in grey letters are from adjoining exons. The * identifies conserved amino acids. Exon numbering is based on the murine sequences. B, C: Putative nuclear localization (B) and export (C) signals in Mtss1 are evolutionary conserved. B: Alignment of part of the IMD domain-sequences of Mtss1 and its structural relatives IRSp53 (also known as Baiap2) and Baiap2l1. The two nuclear localization signals identified are marked by a gray background. Basic amino acids are labeled red, and potential phosphorylation sites are marked green. The basic amino acids binding actin are marked by a yellow background. Note that these are conserved among Mtss1, IRSp53, and Baiap2l1, whereas the nuclear localization signal is found only in Mtss1, and a set of arthropod proteins which share the IMD domain of the Mtss1 type, but diverge from Mtss1 C-terminally. Note also that the nuclear localization signal centered about the basic, actin filament binding motif is immediately adjacent to the four amino acids encoded by exon 7 (shown in gray). C: The leucine-rich motif constituting a putative nuclear export signal inside the IMD is highly conserved for Mtss1. It is not found in the structural homologue, IRSp53. Also shown is the phylogenetic conservation of the nuclear export signal (NES) outside the IMD, which, in the mouse, is encoded by exon 14.
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Figure 5: A: Sequence comparison of exon 12a of Mtss1 in various mammals. Sequence rendered in grey letters are from adjoining exons. The * identifies conserved amino acids. Exon numbering is based on the murine sequences. B, C: Putative nuclear localization (B) and export (C) signals in Mtss1 are evolutionary conserved. B: Alignment of part of the IMD domain-sequences of Mtss1 and its structural relatives IRSp53 (also known as Baiap2) and Baiap2l1. The two nuclear localization signals identified are marked by a gray background. Basic amino acids are labeled red, and potential phosphorylation sites are marked green. The basic amino acids binding actin are marked by a yellow background. Note that these are conserved among Mtss1, IRSp53, and Baiap2l1, whereas the nuclear localization signal is found only in Mtss1, and a set of arthropod proteins which share the IMD domain of the Mtss1 type, but diverge from Mtss1 C-terminally. Note also that the nuclear localization signal centered about the basic, actin filament binding motif is immediately adjacent to the four amino acids encoded by exon 7 (shown in gray). C: The leucine-rich motif constituting a putative nuclear export signal inside the IMD is highly conserved for Mtss1. It is not found in the structural homologue, IRSp53. Also shown is the phylogenetic conservation of the nuclear export signal (NES) outside the IMD, which, in the mouse, is encoded by exon 14.

Mentions: A BLAST search of the NCBI nr database using the murine Mtss1 exon 12a as input identified highly conserved, full-length matching sequences in the Mtss1 genes of several mammals (Fig 5A), but not in non-mammalian genomes. Indeed, the sequence and the exon/intron structure of Mtss1 in xenopus tropicalis and danio rerio (cf Ensemble.org) substantially divergence from that of mammal and chick, over the region comprising exons 12 and 12a in these species, such that an alignment of these regions seem not sensibly possible. This contrasts with the highly conserved structure over the IMD, and also over more C-terminal parts of Mtss1 across species.


Developmental expression and differentiation-related neuron-specific splicing of metastasis suppressor 1 (Mtss1) in normal and transformed cerebellar cells.

Glassmann A, Molly S, Surchev L, Nazwar TA, Holst M, Hartmann W, Baader SL, Oberdick J, Pietsch T, Schilling K - BMC Dev. Biol. (2007)

A: Sequence comparison of exon 12a of Mtss1 in various mammals. Sequence rendered in grey letters are from adjoining exons. The * identifies conserved amino acids. Exon numbering is based on the murine sequences. B, C: Putative nuclear localization (B) and export (C) signals in Mtss1 are evolutionary conserved. B: Alignment of part of the IMD domain-sequences of Mtss1 and its structural relatives IRSp53 (also known as Baiap2) and Baiap2l1. The two nuclear localization signals identified are marked by a gray background. Basic amino acids are labeled red, and potential phosphorylation sites are marked green. The basic amino acids binding actin are marked by a yellow background. Note that these are conserved among Mtss1, IRSp53, and Baiap2l1, whereas the nuclear localization signal is found only in Mtss1, and a set of arthropod proteins which share the IMD domain of the Mtss1 type, but diverge from Mtss1 C-terminally. Note also that the nuclear localization signal centered about the basic, actin filament binding motif is immediately adjacent to the four amino acids encoded by exon 7 (shown in gray). C: The leucine-rich motif constituting a putative nuclear export signal inside the IMD is highly conserved for Mtss1. It is not found in the structural homologue, IRSp53. Also shown is the phylogenetic conservation of the nuclear export signal (NES) outside the IMD, which, in the mouse, is encoded by exon 14.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2194783&req=5

Figure 5: A: Sequence comparison of exon 12a of Mtss1 in various mammals. Sequence rendered in grey letters are from adjoining exons. The * identifies conserved amino acids. Exon numbering is based on the murine sequences. B, C: Putative nuclear localization (B) and export (C) signals in Mtss1 are evolutionary conserved. B: Alignment of part of the IMD domain-sequences of Mtss1 and its structural relatives IRSp53 (also known as Baiap2) and Baiap2l1. The two nuclear localization signals identified are marked by a gray background. Basic amino acids are labeled red, and potential phosphorylation sites are marked green. The basic amino acids binding actin are marked by a yellow background. Note that these are conserved among Mtss1, IRSp53, and Baiap2l1, whereas the nuclear localization signal is found only in Mtss1, and a set of arthropod proteins which share the IMD domain of the Mtss1 type, but diverge from Mtss1 C-terminally. Note also that the nuclear localization signal centered about the basic, actin filament binding motif is immediately adjacent to the four amino acids encoded by exon 7 (shown in gray). C: The leucine-rich motif constituting a putative nuclear export signal inside the IMD is highly conserved for Mtss1. It is not found in the structural homologue, IRSp53. Also shown is the phylogenetic conservation of the nuclear export signal (NES) outside the IMD, which, in the mouse, is encoded by exon 14.
Mentions: A BLAST search of the NCBI nr database using the murine Mtss1 exon 12a as input identified highly conserved, full-length matching sequences in the Mtss1 genes of several mammals (Fig 5A), but not in non-mammalian genomes. Indeed, the sequence and the exon/intron structure of Mtss1 in xenopus tropicalis and danio rerio (cf Ensemble.org) substantially divergence from that of mammal and chick, over the region comprising exons 12 and 12a in these species, such that an alignment of these regions seem not sensibly possible. This contrasts with the highly conserved structure over the IMD, and also over more C-terminal parts of Mtss1 across species.

Bottom Line: In the adult CNS, Mtss1 is found exclusively in cerebellar Purkinje cells.Both the pattern of expression and splicing of Mtss1 is developmentally regulated in the murine cerebellum.These findings are discussed with a view on the potential role of Mtss1 for cytoskeletal dynamics in developing and mature cerebellar neurons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Anatomisches Institut, Anatomie & Zellbiologie, University of Bonn, Bonn, Germany. alexander.glassmann@uni-bonn.de

ABSTRACT

Background: Mtss1 encodes an actin-binding protein, dysregulated in a variety of tumors, that interacts with sonic hedgehog/Gli signaling in epidermal cells. Given the prime importance of this pathway for cerebellar development and tumorigenesis, we assessed expression of Mtss1 in the developing murine cerebellum and human medulloblastoma specimens.

Results: During development, Mtss1 is transiently expressed in granule cells, from the time point they cease to proliferate to their synaptic integration. It is also expressed by granule cell precursor-derived medulloblastomas. In the adult CNS, Mtss1 is found exclusively in cerebellar Purkinje cells. Neuronal differentiation is accompanied by a switch in Mtss1 splicing. Whereas immature granule cells express a Mtss1 variant observed also in peripheral tissues and comprising exon 12, this exon is replaced by a CNS-specific exon, 12a, in more mature granule cells and in adult Purkinje cells. Bioinformatic analysis of Mtss1 suggests that differential exon usage may affect interaction with Fyn and Src, two tyrosine kinases previously recognized as critical for cerebellar cell migration and histogenesis. Further, this approach led to the identification of two evolutionary conserved nuclear localization sequences. These overlap with the actin filament binding site of Mtss1, and one also harbors a potential PKA and PKC phosphorylation site.

Conclusion: Both the pattern of expression and splicing of Mtss1 is developmentally regulated in the murine cerebellum. These findings are discussed with a view on the potential role of Mtss1 for cytoskeletal dynamics in developing and mature cerebellar neurons.

Show MeSH
Related in: MedlinePlus