The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways.
BACKGROUND
Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown.


RESULTS
Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-beta signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice.


CONCLUSIONS
Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-beta signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-beta signaling and connective tissue dysfunction.
Fukada
Toshiyuki
T
Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Tsurumi, Yokohama, Kanagawa, Japan.
Civic
Natacha
N
Furuichi
Tatsuya
T
Shimoda
Shinji
S
Mishima
Kenji
K
Higashiyama
Hiroyuki
H
Idaira
Yayoi
Y
Asada
Yoshinobu
Y
Kitamura
Hiroshi
H
Yamasaki
Satoru
S
Hojyo
Shintaro
S
Nakayama
Manabu
M
Ohara
Osamu
O
Koseki
Haruhiko
H
Dos Santos
Heloisa G
HG
Bonafe
Luisa
L
Ha-Vinh
Russia
R
Zankl
Andreas
A
Unger
Sheila
S
Kraenzlin
Marius E
ME
Beckmann
Jacques S
JS
Saito
Ichiro
I
Rivolta
Carlo
C
Ikegawa
Shiro
S
Superti-Furga
Andrea
A
Hirano
Toshio
T
D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D003238:Connective Tissue / Q000254:growth & development* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004535:Ehlers-Danlos Syndrome / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics; D010012:Osteogenesis / Q000235:genetics; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D055815:Young Adult; D015032:Zinc / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D027682:Cation Transport Proteins; C521172:SLC39A13 protein, human; D016212:Transforming Growth Factor beta; D015032:Zinc