miRNAs control tracheal chondrocyte differentiation

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.

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► Loss of Dicer1 activity in Col2a1 chondrocytes causes lethal tracheomalacia.
► Without miRNAs, Aggrecan / Collagen-2a1 expression in chondrocytes is downregulated.
► Snail1, an unwanted transcriptional repressor is upregulated in Dicer1 KO trachea.
► miR-125b and miR-30a/c silence Snail1 in tracheal chondrocytes.