Abnormal epidermal differentiation and impaired epithelial-mesenchymal tissue interactions in mice lacking the retinoblastoma relatives p107 and p130.
The functions of p107 and p130, members of the retinoblastoma family, include the control of cell cycle progression and differentiation in several tissues. Our previous studies suggested a role for p107 and p130 in keratinocyte differentiation in vitro. We now extend these data using knockout animal models. We found impaired terminal differentiation in the interfollicular keratinocytes of p107/p130-double-null mice epidermis. In addition, we observed a decreased number of hair follicles and a clear developmental delay in hair, whiskers and tooth germs. Skin grafts of p107/p130-deficient epidermis onto NOD/scid mice showed altered differentiation and hyperproliferation of the interfollicular keratinocytes, thus demonstrating that the absence of p107 and p130 results in the deficient control of differentiation in keratinocytes in a cell-autonomous manner. Besides normal hair formation, follicular cysts, misoriented and dysplastic follicles, together with aberrant hair cycling, were also observed in the p107/p130 skin transplants. Finally, the hair abnormalities in p107/p130-null skin were associated with altered Bmp4-dependent signaling including decreased DeltaNp63 expression. These results indicate an essential role for p107 and p130 in the epithelial-mesenchimal interactions.
Ruiz
Sergio
S
Program on Cell and Molecular Biology and Gene Therapy. CIEMAT, Avenue Complutense 22, E28040 Madrid, Spain.
Segrelles
Carmen
C
Bravo
Ana
A
Santos
Mirentxu
M
Perez
Paloma
P
Leis
Hugo
H
Jorcano
Jose L
JL
Paramio
Jesús M
JM
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics; D004817:Epidermis / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D018859:Hair Follicle / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011506:Proteins; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D012868:Skin Abnormalities / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016038:Skin Transplantation; D014083:Tooth Germ / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins