TY - JOUR
T1 - Epidermal hyperproliferation in mice lacking fatty acid transport protein 4 (FATP4) involves ectopic EGF receptor and STAT3 signaling
AU - Lin, Meei Hua
AU - Chang, Kuo Wei
AU - Lin, Shu Chun
AU - Miner, Jeffrey H.
N1 - Funding Information:
We thank Cheng-Hwang Perng, Bioinformatics Center, National Yang-Ming University for quality check and statistical analyses of the array data. We are grateful to: Seth Blackshaw for important suggestions on the in situ hybridization protocol; Darlene Stewart and Teresa Tolley of the Pulmonary Morphology Core (supported by NIH P01HL029594 ) for assistance with histology; Jennifer Richardson for genotyping mice; the Mouse Genetics Core for husbandry services; the Renal Disease Models Core ( NIH P30DK079333 ) for qPCR and imaging support; and Raphael Kopan for critical comments on the manuscript. This work was supported by NIH R01AR049269 (to JHM) and by NSC93-3112-B-010-001 (to SCL). Mice were housed in a facility supported by NIH C06RR015502.
PY - 2010/8
Y1 - 2010/8
N2 - Fatty acid transport protein (FATP) 4 is one of a family of six FATPs that facilitate long- and very long-chain fatty acid uptake. Mice lacking FATP4 are born with tight, thick skin and a defective epidermal barrier; they die neonatally due to dehydration and restricted movements. Both the skin phenotype and the lethality are rescued by transgene-driven expression of FATP4 solely in suprabasal keratinocytes. Here we show that Fatp4 mutants exhibit epidermal hyperplasia resulting from an increased number of proliferating suprabasal cells. In addition, barrier formation initiates precociously but never progresses to completion. To investigate possible mechanisms whereby Fatp4 influences skin development, we identified misregulated genes in Fatp4 mutants. Remarkably, three members of the epidermal growth factor (EGF) family (Ereg, Areg, and Epgn) showed increased expression that was associated with elevated epidermal activation of the EGF receptor (EGFR) and STAT3, a downstream effector of EGFR signaling. Both Tyrphostin AG1478, an EGFR tyrosine kinase inhibitor, and curcumin, an inhibitor of both STAT3 and EGFR, attenuated STAT3 activation/nuclear translocation, reduced skin thickening, and partially suppressed the barrier abnormalities. These data identify FATP4 activity as negatively influencing EGFR activation and the resulting STAT3 signaling during normal skin development. These findings have important implications for understanding the pathogenesis of ichthyosis prematurity syndrome, a disease recently shown to be caused by FATP4 mutations.
AB - Fatty acid transport protein (FATP) 4 is one of a family of six FATPs that facilitate long- and very long-chain fatty acid uptake. Mice lacking FATP4 are born with tight, thick skin and a defective epidermal barrier; they die neonatally due to dehydration and restricted movements. Both the skin phenotype and the lethality are rescued by transgene-driven expression of FATP4 solely in suprabasal keratinocytes. Here we show that Fatp4 mutants exhibit epidermal hyperplasia resulting from an increased number of proliferating suprabasal cells. In addition, barrier formation initiates precociously but never progresses to completion. To investigate possible mechanisms whereby Fatp4 influences skin development, we identified misregulated genes in Fatp4 mutants. Remarkably, three members of the epidermal growth factor (EGF) family (Ereg, Areg, and Epgn) showed increased expression that was associated with elevated epidermal activation of the EGF receptor (EGFR) and STAT3, a downstream effector of EGFR signaling. Both Tyrphostin AG1478, an EGFR tyrosine kinase inhibitor, and curcumin, an inhibitor of both STAT3 and EGFR, attenuated STAT3 activation/nuclear translocation, reduced skin thickening, and partially suppressed the barrier abnormalities. These data identify FATP4 activity as negatively influencing EGFR activation and the resulting STAT3 signaling during normal skin development. These findings have important implications for understanding the pathogenesis of ichthyosis prematurity syndrome, a disease recently shown to be caused by FATP4 mutations.
KW - Amphiregulin
KW - Epidermal hyperplasia
KW - Epiregulin
KW - Epithelial mitogen
KW - PPAR
KW - Skin barrier
UR - http://www.scopus.com/inward/record.url?scp=77955269825&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2010.05.503
DO - 10.1016/j.ydbio.2010.05.503
M3 - Article
C2 - 20513444
AN - SCOPUS:77955269825
SN - 0012-1606
VL - 344
SP - 707
EP - 719
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -