TY - JOUR
T1 - MiRNAs control tracheal chondrocyte differentiation
AU - Gradus, Ben
AU - Alon, Ilana
AU - Hornstein, Eran
N1 - Israel Science Foundation; Minerva-Weizmann Program; Estate of Flourence Blau; Wolfson Family Charitable trust and Yeda/SelaThe Dicer1 conditional allele is the kind gift of Mike McManus, Brian Harfe and Cliff Tabin. miRNA expression vectors were generously provided by Reuven Agami and ATDC5 cells by Moshe Phillip. The Snail1 expression vector is the kind gift of Olivier Pourquie. We thank M. Angela Nieto for discussions; Elazar Zelzer and Cliff Tabin for insightful remarks on the manuscript and Cherill Banks for English editing. We thank On Brenner for assistance with histopathology, Judith Chermesh, Zamir Kohavi and Neria Sharabi for mouse husbandry. EH is the incumbent of the Helen and Milton A. Kimmelman Career Development Chair. This work was supported by research grants to EH from the Israel Science Foundation, the Minerva-Weizmann Program, the Estate of Flourence Blau, Wolfson Family Charitable trust and Yeda/Sela.
PY - 2011/12/1
Y1 - 2011/12/1
N2 - The specific program that enables the stereotypic differentiation of specialized cartilages, including the trachea, is intrinsically distinct from the program that gives rise to growth plate hypertrophic chondrocytes. For example, Snail1 is an effector of FGF signaling in growth plate pre-hypertrophic chondrocytes, but it derails the normal program of permanent chondrocytes, repressing the transcription of Aggrecan and Collagen type 2a1 (Col2a1). Here we show that miRNA activity is essential for normal trachea development and that miR-125b and miR-30a/c keep Snail1 at low levels, thus enabling full functional differentiation of Col2a1 tracheal chondrocytes. Specific inhibition of miR-125b and miR-30a/c in chondrocytes or Dicer1 knockout in the trachea, de-repress Snail1. As a consequence, the transcription of Aggrecan and Col2a1 is hampered and extracellular matrix deposition is decreased. Our data reveals a new miRNA pathway that is safekeeping the specific genetic program of differentiated and matrix-producing tracheal chondrocytes from acquisition of unwanted signals. This pathway may improve understanding of human primary tracheomalacia and improve protocols for cartilage tissue engineering.
AB - The specific program that enables the stereotypic differentiation of specialized cartilages, including the trachea, is intrinsically distinct from the program that gives rise to growth plate hypertrophic chondrocytes. For example, Snail1 is an effector of FGF signaling in growth plate pre-hypertrophic chondrocytes, but it derails the normal program of permanent chondrocytes, repressing the transcription of Aggrecan and Collagen type 2a1 (Col2a1). Here we show that miRNA activity is essential for normal trachea development and that miR-125b and miR-30a/c keep Snail1 at low levels, thus enabling full functional differentiation of Col2a1 tracheal chondrocytes. Specific inhibition of miR-125b and miR-30a/c in chondrocytes or Dicer1 knockout in the trachea, de-repress Snail1. As a consequence, the transcription of Aggrecan and Col2a1 is hampered and extracellular matrix deposition is decreased. Our data reveals a new miRNA pathway that is safekeeping the specific genetic program of differentiated and matrix-producing tracheal chondrocytes from acquisition of unwanted signals. This pathway may improve understanding of human primary tracheomalacia and improve protocols for cartilage tissue engineering.
UR - http://www.scopus.com/inward/record.url?scp=80755153157&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2011.09.002
DO - 10.1016/j.ydbio.2011.09.002
M3 - مقالة
SN - 0012-1606
VL - 360
SP - 58
EP - 65
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -