Genetic interactions support an inhibitory relationship between bone morphogenetic protein 2 and netrin 1 during semicircular canal formation

Development. 2019 Feb 15;146(4):dev174748. doi: 10.1242/dev.174748.


The semicircular canals of the mammalian inner ear are derived from epithelial pouches in which epithelial cells in the central region of each pouch undergo resorption, leaving behind the region at the rim to form a tube-shaped canal. Lack of proliferation at the rim and/or over-clearing of epithelial cells in the center of the pouch can obliterate canal formation. Otic-specific knockout of bone morphogenetic protein 2 (Bmp2) results in absence of all three semicircular canals; however, the common crus and ampullae housing the sensory tissue (crista) are intact. The lack of Bmp2 causes Ntn1 (which encodes netrin 1), which is required for canal resorption, to be ectopically expressed at the canal rim. Ectopic Ntn1 results in reduction of Dlx5 and Lmo4, which are required for rim formation. These phenotypes can be partially rescued by removing one allele of Ntn1 in the Bmp2 mutants, indicating that Bmp2 normally negatively regulates Ntn1 for canal formation. Additionally, non-resorption of the canal pouch in Ntn1-/- mutants is partially rescued by removing one allele of Bmp2 Thus, reciprocal inhibition between Bmp2 and netrin 1 is involved in canal formation of the vestibule.

Keywords: Inner ear; Morphogenesis; Mouse; Patterning.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Alleles
  • Animals
  • Bone Morphogenetic Protein 2 / genetics*
  • Bone Morphogenetic Protein 2 / metabolism
  • Cell Lineage
  • Cell Proliferation
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Genotype
  • Homeodomain Proteins / metabolism
  • LIM Domain Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Nerve Tissue Proteins / metabolism
  • Netrin-1 / genetics*
  • Netrin-1 / metabolism
  • Phenotype
  • Protein Binding
  • Protein Domains
  • Semicircular Canals / embryology*
  • Vestibule, Labyrinth / embryology


  • Adaptor Proteins, Signal Transducing
  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Dlx5 protein, mouse
  • Forkhead Transcription Factors
  • Foxg1 protein, mouse
  • Homeodomain Proteins
  • LIM Domain Proteins
  • Lmo4 protein, mouse
  • Nerve Tissue Proteins
  • Ntn1 protein, mouse
  • Netrin-1