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Comparative genomic analysis of slc39a12/ZIP12: insight into a zinc transporter required for vertebrate nervous system development.

Chowanadisai W - PLoS ONE (2014)

Bottom Line: The hypothesis that ZIP12 is a zinc transporter important for nervous system function and development guided a comparative genetics approach to uncover the presence of ZIP12 in various genomes and identify conserved sequences and expression patterns associated with ZIP12.The discrimination of ZIP12 compared to ZIP4 was unsuccessful or inconclusive in other invertebrate chordates and deuterostomes.Consequently, the role of ZIP12 may be an important link to reported congenital malformations in numerous animal models and humans that are caused by zinc deficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutrition, University of California Davis, Davis, California, United States of America.

ABSTRACT
The zinc transporter ZIP12, which is encoded by the gene slc39a12, has previously been shown to be important for neuronal differentiation in mouse Neuro-2a neuroblastoma cells and primary mouse neurons and necessary for neurulation during Xenopus tropicalis embryogenesis. However, relatively little is known about the biochemical properties, cellular regulation, or the physiological role of this gene. The hypothesis that ZIP12 is a zinc transporter important for nervous system function and development guided a comparative genetics approach to uncover the presence of ZIP12 in various genomes and identify conserved sequences and expression patterns associated with ZIP12. Ortholog detection of slc39a12 was conducted with reciprocal BLAST hits with the amino acid sequence of human ZIP12 in comparison to the human paralog ZIP4 and conserved local synteny between genomes. ZIP12 is present in the genomes of almost all vertebrates examined, from humans and other mammals to most teleost fish. However, ZIP12 appears to be absent from the zebrafish genome. The discrimination of ZIP12 compared to ZIP4 was unsuccessful or inconclusive in other invertebrate chordates and deuterostomes. Splice variation, due to the inclusion or exclusion of a conserved exon, is present in humans, rats, and cows and likely has biological significance. ZIP12 also possesses many putative di-leucine and tyrosine motifs often associated with intracellular trafficking, which may control cellular zinc uptake activity through the localization of ZIP12 within the cell. These findings highlight multiple aspects of ZIP12 at the biochemical, cellular, and physiological levels with likely biological significance. ZIP12 appears to have conserved function as a zinc uptake transporter in vertebrate nervous system development. Consequently, the role of ZIP12 may be an important link to reported congenital malformations in numerous animal models and humans that are caused by zinc deficiency.

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Rat slc39a12 mRNA and translated protein sequences derived from EST and genome analyses.Full sequence was formed from rat EST [GenBank: FM065041], genome sequence [GenBank: NW_047496, nucleotides 3955687-3955698], and current annotated entry for rat slc39a12 [GenBank: NM_001106124]. The additional N-terminus amino acid sequence is shaded gray. Stop codon (opal) upstream of putative start codon is shaded black.
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pone-0111535-g006: Rat slc39a12 mRNA and translated protein sequences derived from EST and genome analyses.Full sequence was formed from rat EST [GenBank: FM065041], genome sequence [GenBank: NW_047496, nucleotides 3955687-3955698], and current annotated entry for rat slc39a12 [GenBank: NM_001106124]. The additional N-terminus amino acid sequence is shaded gray. Stop codon (opal) upstream of putative start codon is shaded black.

Mentions: There are possible mechanisms outside the coding sequence which may control the tissue-specific expression of slc39a12 in vertebrates and are likely conserved. The 3′ untranslated region of ZIP12 in many species is adenine/uracil (A/U) rich (Table 2). The 3′ UTRs of many brain-specific genes are A/U rich [76]. There are proteins that can affect mRNA stability by binding to these A/U rich regions [77], which may account for the high expression of ZIP12 in the nervous system. An alignment of the 5′ UTR, the first 90 bp of the coding sequence, and the proximal promoter (1000 bp upstream of the transcription start site) (Figure 5) shows that there are areas of sequence conservation. A scan of the human proximal promoter combined with an alignment of the sequences with cow and mouse shows that there are putative transcription binding sites for AP-1, Evi-1, FoxD3, and COMP1 (Figure 6). It is possible that the N-terminus encodes a signal peptide, and the prediction software SignalP [78] indicates that there may be a cleavage site between amino acids 23–24 or 26–27 (Figure 5). In contrast to many genes important for neuronal development [79], the 5′ UTR and proximal promoter are not guanine/cytosine (GC) rich (GC content: human 44.8%; mouse 39.3%; cow 39.8%), and there was no difference in GC content between the 5′ UTR (41.8%) and proximal promoter (45.6%) of the human slc39a12 gene. More analyses, possibly combined with biological experimentation, will be needed to determine if the 5′ UTR, 3′ UTR, or nearby upstream portions contribute towards the high expression of ZIP12 in the nervous system. As an example of how regulatory elements can control zinc uptake transporter expression, active metal-response elements have been identified in the 5′ UTR of zinc transporter genes in mice and zebrafish [80], [81]. Because there are possible conserved elements in the distal promoter and some intronic regions, as indicated by PhyloP and PhastCons (Figure 2), these areas may also contribute towards the distinct pattern of ZIP12 expression in the vertebrate nervous system and the possible regulatory subfunctionalization of ZIP12 and close paralogs. The tissue specificity of slc39a12 in these species and previous findings showing enriched expression of slc39a12 in vertebrate brains [21] support a role for ZIP12 in the central nervous system.


Comparative genomic analysis of slc39a12/ZIP12: insight into a zinc transporter required for vertebrate nervous system development.

Chowanadisai W - PLoS ONE (2014)

Rat slc39a12 mRNA and translated protein sequences derived from EST and genome analyses.Full sequence was formed from rat EST [GenBank: FM065041], genome sequence [GenBank: NW_047496, nucleotides 3955687-3955698], and current annotated entry for rat slc39a12 [GenBank: NM_001106124]. The additional N-terminus amino acid sequence is shaded gray. Stop codon (opal) upstream of putative start codon is shaded black.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222902&req=5

pone-0111535-g006: Rat slc39a12 mRNA and translated protein sequences derived from EST and genome analyses.Full sequence was formed from rat EST [GenBank: FM065041], genome sequence [GenBank: NW_047496, nucleotides 3955687-3955698], and current annotated entry for rat slc39a12 [GenBank: NM_001106124]. The additional N-terminus amino acid sequence is shaded gray. Stop codon (opal) upstream of putative start codon is shaded black.
Mentions: There are possible mechanisms outside the coding sequence which may control the tissue-specific expression of slc39a12 in vertebrates and are likely conserved. The 3′ untranslated region of ZIP12 in many species is adenine/uracil (A/U) rich (Table 2). The 3′ UTRs of many brain-specific genes are A/U rich [76]. There are proteins that can affect mRNA stability by binding to these A/U rich regions [77], which may account for the high expression of ZIP12 in the nervous system. An alignment of the 5′ UTR, the first 90 bp of the coding sequence, and the proximal promoter (1000 bp upstream of the transcription start site) (Figure 5) shows that there are areas of sequence conservation. A scan of the human proximal promoter combined with an alignment of the sequences with cow and mouse shows that there are putative transcription binding sites for AP-1, Evi-1, FoxD3, and COMP1 (Figure 6). It is possible that the N-terminus encodes a signal peptide, and the prediction software SignalP [78] indicates that there may be a cleavage site between amino acids 23–24 or 26–27 (Figure 5). In contrast to many genes important for neuronal development [79], the 5′ UTR and proximal promoter are not guanine/cytosine (GC) rich (GC content: human 44.8%; mouse 39.3%; cow 39.8%), and there was no difference in GC content between the 5′ UTR (41.8%) and proximal promoter (45.6%) of the human slc39a12 gene. More analyses, possibly combined with biological experimentation, will be needed to determine if the 5′ UTR, 3′ UTR, or nearby upstream portions contribute towards the high expression of ZIP12 in the nervous system. As an example of how regulatory elements can control zinc uptake transporter expression, active metal-response elements have been identified in the 5′ UTR of zinc transporter genes in mice and zebrafish [80], [81]. Because there are possible conserved elements in the distal promoter and some intronic regions, as indicated by PhyloP and PhastCons (Figure 2), these areas may also contribute towards the distinct pattern of ZIP12 expression in the vertebrate nervous system and the possible regulatory subfunctionalization of ZIP12 and close paralogs. The tissue specificity of slc39a12 in these species and previous findings showing enriched expression of slc39a12 in vertebrate brains [21] support a role for ZIP12 in the central nervous system.

Bottom Line: The hypothesis that ZIP12 is a zinc transporter important for nervous system function and development guided a comparative genetics approach to uncover the presence of ZIP12 in various genomes and identify conserved sequences and expression patterns associated with ZIP12.The discrimination of ZIP12 compared to ZIP4 was unsuccessful or inconclusive in other invertebrate chordates and deuterostomes.Consequently, the role of ZIP12 may be an important link to reported congenital malformations in numerous animal models and humans that are caused by zinc deficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutrition, University of California Davis, Davis, California, United States of America.

ABSTRACT
The zinc transporter ZIP12, which is encoded by the gene slc39a12, has previously been shown to be important for neuronal differentiation in mouse Neuro-2a neuroblastoma cells and primary mouse neurons and necessary for neurulation during Xenopus tropicalis embryogenesis. However, relatively little is known about the biochemical properties, cellular regulation, or the physiological role of this gene. The hypothesis that ZIP12 is a zinc transporter important for nervous system function and development guided a comparative genetics approach to uncover the presence of ZIP12 in various genomes and identify conserved sequences and expression patterns associated with ZIP12. Ortholog detection of slc39a12 was conducted with reciprocal BLAST hits with the amino acid sequence of human ZIP12 in comparison to the human paralog ZIP4 and conserved local synteny between genomes. ZIP12 is present in the genomes of almost all vertebrates examined, from humans and other mammals to most teleost fish. However, ZIP12 appears to be absent from the zebrafish genome. The discrimination of ZIP12 compared to ZIP4 was unsuccessful or inconclusive in other invertebrate chordates and deuterostomes. Splice variation, due to the inclusion or exclusion of a conserved exon, is present in humans, rats, and cows and likely has biological significance. ZIP12 also possesses many putative di-leucine and tyrosine motifs often associated with intracellular trafficking, which may control cellular zinc uptake activity through the localization of ZIP12 within the cell. These findings highlight multiple aspects of ZIP12 at the biochemical, cellular, and physiological levels with likely biological significance. ZIP12 appears to have conserved function as a zinc uptake transporter in vertebrate nervous system development. Consequently, the role of ZIP12 may be an important link to reported congenital malformations in numerous animal models and humans that are caused by zinc deficiency.

Show MeSH
Related in: MedlinePlus