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TMEM203 Is a Novel Regulator of Intracellular Calcium Homeostasis and Is Required for Spermatogenesis.

Shambharkar PB, Bittinger M, Latario B, Xiong Z, Bandyopadhyay S, Davis V, Lin V, Yang Y, Valdez R, Labow MA - PLoS ONE (2015)

Bottom Line: TMEM203 protein was localized to the ER and found associated with a number of ER proteins which regulate ER calcium entry and efflux.Mouse Embryonic Fibroblasts (MEFs) derived from Tmem203 deficient mice had reduced ER calcium stores and altered calcium homeostasis.Tmem203 deficient mice were viable though male knockout mice were infertile and exhibited a severe block in spermiogenesis and spermiation.

View Article: PubMed Central - PubMed

Affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, 100 Technology Square, Cambridge, Massachusetts, United States of America.

ABSTRACT
Intracellular calcium signaling is critical for initiating and sustaining diverse cellular functions including transcription, synaptic signaling, muscle contraction, apoptosis and fertilization. Trans-membrane 203 (TMEM203) was identified here in cDNA overexpression screens for proteins capable of modulating intracellular calcium levels using activation of a calcium/calcineurin regulated transcription factor as an indicator. Overexpression of TMEM203 resulted in a reduction of Endoplasmic Reticulum (ER) calcium stores and elevation in basal cytoplasmic calcium levels. TMEM203 protein was localized to the ER and found associated with a number of ER proteins which regulate ER calcium entry and efflux. Mouse Embryonic Fibroblasts (MEFs) derived from Tmem203 deficient mice had reduced ER calcium stores and altered calcium homeostasis. Tmem203 deficient mice were viable though male knockout mice were infertile and exhibited a severe block in spermiogenesis and spermiation. Expression profiling studies showed significant alternations in expression of calcium channels and pumps in testes and concurrently Tmem203 deficient spermatocytes demonstrated significantly altered calcium handling. Thus Tmem203 is an evolutionarily conserved regulator of cellular calcium homeostasis, is required for spermatogenesis and provides a causal link between intracellular calcium regulation and spermiogenesis.

No MeSH data available.


Related in: MedlinePlus

Tmem203  mice completely lack mature spermatozoa in epididymis.(A) Computer assisted sperm analyzer based analysis of epididymis preparations from wild type and Tmem203  mice showed complete absence (*) of mature spermatozoa in Tmem203  mice. Data is representative of two independent experiments. (B) Representative photomicrographs illustrating hematoxylin and eosin (H&E)-stained sections of proximal epididymis (caput; upper left and right panels) and distal epididymis (cauda; lower left and right panels) from a 48-week-old wild type mouse (upper and lower left panels) and from a 48-week-old Tmem203  mice (upper and lower right panels). Note the complete absence of mature spermatozoa in the epididymis of the Tmem203  mice compared to the wild type mice in which numerous mature spermatozoa are observed; tubular lumina of the epididymis from Tmem203  mice contains eosinophilic proteinaceous material mixed with cellular debris. Scale bars = 50 μm.
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pone.0127480.g004: Tmem203 mice completely lack mature spermatozoa in epididymis.(A) Computer assisted sperm analyzer based analysis of epididymis preparations from wild type and Tmem203 mice showed complete absence (*) of mature spermatozoa in Tmem203 mice. Data is representative of two independent experiments. (B) Representative photomicrographs illustrating hematoxylin and eosin (H&E)-stained sections of proximal epididymis (caput; upper left and right panels) and distal epididymis (cauda; lower left and right panels) from a 48-week-old wild type mouse (upper and lower left panels) and from a 48-week-old Tmem203 mice (upper and lower right panels). Note the complete absence of mature spermatozoa in the epididymis of the Tmem203 mice compared to the wild type mice in which numerous mature spermatozoa are observed; tubular lumina of the epididymis from Tmem203 mice contains eosinophilic proteinaceous material mixed with cellular debris. Scale bars = 50 μm.

Mentions: Tmem203 deficient mice lacked mature spermatozoa (complete azoospermia) as detected by a computer assisted sperm analyzer (CASA: Fig 4A). Histologic evaluation of the epididymides harvested from either 38-week-old or 48-week-old male Tmem203 deficient mice also showed a complete lack of mature spermatozoa in the epididymides (azoospermia) compared to wild type mice (Fig 4B). No abnormalities were seen in Tmem203 heterozygous mice (data not shown).


TMEM203 Is a Novel Regulator of Intracellular Calcium Homeostasis and Is Required for Spermatogenesis.

Shambharkar PB, Bittinger M, Latario B, Xiong Z, Bandyopadhyay S, Davis V, Lin V, Yang Y, Valdez R, Labow MA - PLoS ONE (2015)

Tmem203  mice completely lack mature spermatozoa in epididymis.(A) Computer assisted sperm analyzer based analysis of epididymis preparations from wild type and Tmem203  mice showed complete absence (*) of mature spermatozoa in Tmem203  mice. Data is representative of two independent experiments. (B) Representative photomicrographs illustrating hematoxylin and eosin (H&E)-stained sections of proximal epididymis (caput; upper left and right panels) and distal epididymis (cauda; lower left and right panels) from a 48-week-old wild type mouse (upper and lower left panels) and from a 48-week-old Tmem203  mice (upper and lower right panels). Note the complete absence of mature spermatozoa in the epididymis of the Tmem203  mice compared to the wild type mice in which numerous mature spermatozoa are observed; tubular lumina of the epididymis from Tmem203  mice contains eosinophilic proteinaceous material mixed with cellular debris. Scale bars = 50 μm.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4440627&req=5

pone.0127480.g004: Tmem203 mice completely lack mature spermatozoa in epididymis.(A) Computer assisted sperm analyzer based analysis of epididymis preparations from wild type and Tmem203 mice showed complete absence (*) of mature spermatozoa in Tmem203 mice. Data is representative of two independent experiments. (B) Representative photomicrographs illustrating hematoxylin and eosin (H&E)-stained sections of proximal epididymis (caput; upper left and right panels) and distal epididymis (cauda; lower left and right panels) from a 48-week-old wild type mouse (upper and lower left panels) and from a 48-week-old Tmem203 mice (upper and lower right panels). Note the complete absence of mature spermatozoa in the epididymis of the Tmem203 mice compared to the wild type mice in which numerous mature spermatozoa are observed; tubular lumina of the epididymis from Tmem203 mice contains eosinophilic proteinaceous material mixed with cellular debris. Scale bars = 50 μm.
Mentions: Tmem203 deficient mice lacked mature spermatozoa (complete azoospermia) as detected by a computer assisted sperm analyzer (CASA: Fig 4A). Histologic evaluation of the epididymides harvested from either 38-week-old or 48-week-old male Tmem203 deficient mice also showed a complete lack of mature spermatozoa in the epididymides (azoospermia) compared to wild type mice (Fig 4B). No abnormalities were seen in Tmem203 heterozygous mice (data not shown).

Bottom Line: TMEM203 protein was localized to the ER and found associated with a number of ER proteins which regulate ER calcium entry and efflux.Mouse Embryonic Fibroblasts (MEFs) derived from Tmem203 deficient mice had reduced ER calcium stores and altered calcium homeostasis.Tmem203 deficient mice were viable though male knockout mice were infertile and exhibited a severe block in spermiogenesis and spermiation.

View Article: PubMed Central - PubMed

Affiliation: Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, 100 Technology Square, Cambridge, Massachusetts, United States of America.

ABSTRACT
Intracellular calcium signaling is critical for initiating and sustaining diverse cellular functions including transcription, synaptic signaling, muscle contraction, apoptosis and fertilization. Trans-membrane 203 (TMEM203) was identified here in cDNA overexpression screens for proteins capable of modulating intracellular calcium levels using activation of a calcium/calcineurin regulated transcription factor as an indicator. Overexpression of TMEM203 resulted in a reduction of Endoplasmic Reticulum (ER) calcium stores and elevation in basal cytoplasmic calcium levels. TMEM203 protein was localized to the ER and found associated with a number of ER proteins which regulate ER calcium entry and efflux. Mouse Embryonic Fibroblasts (MEFs) derived from Tmem203 deficient mice had reduced ER calcium stores and altered calcium homeostasis. Tmem203 deficient mice were viable though male knockout mice were infertile and exhibited a severe block in spermiogenesis and spermiation. Expression profiling studies showed significant alternations in expression of calcium channels and pumps in testes and concurrently Tmem203 deficient spermatocytes demonstrated significantly altered calcium handling. Thus Tmem203 is an evolutionarily conserved regulator of cellular calcium homeostasis, is required for spermatogenesis and provides a causal link between intracellular calcium regulation and spermiogenesis.

No MeSH data available.


Related in: MedlinePlus