The Meckel syndrome protein meckelin (TMEM67) is a key regulator of cilia function but is not required for tissue planar polarity

Hum Mol Genet. 2013 May 15;22(10):2024-40. doi: 10.1093/hmg/ddt054. Epub 2013 Feb 7.

Abstract

Meckel syndrome (MKS) is a lethal disorder associated with renal cystic disease, encephalocele, ductal plate malformation and polydactyly. MKS is genetically heterogeneous and part of a growing list of syndromes called ciliopathies, disorders resulting from defective cilia. TMEM67 mutation (MKS3) is a major cause of MKS and the related ciliopathy Joubert syndrome, although the complete etiology of the disease is not well understood. To further investigate MKS3, we analyzed phenotypes in the Tmem67 null mouse (bpck) and in zebrafish tmem67 morphants. Phenotypes similar to those in human MKS and other ciliopathy models were observed, with additional eye, skeletal and inner ear abnormalities characterized in the bpck mouse. The observed disorganized stereociliary bundles in the bpck inner ear and the convergent extension defects in zebrafish morphants are similar to those found in planar cell polarity (PCP) mutants, a pathway suggested to be defective in ciliopathies. However, analysis of classical vertebrate PCP readouts in the bpck mouse and ciliary organization analysis in tmem67 morphants did not support a global loss of planar polarity. Canonical Wnt signaling was upregulated in cyst linings and isolated fibroblasts from the bpck mouse, but was unchanged in the retina and cochlea tissue, suggesting that increased Wnt signaling may only be linked to MKS3 phenotypes associated with elevated proliferation. Together, these data suggest that defective cilia loading, but not a global loss of ciliogenesis, basal body docking or PCP signaling leads to dysfunctional cilia in MKS3 tissues.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple
  • Animals
  • Cell Polarity / physiology*
  • Cerebellar Diseases / embryology
  • Cerebellar Diseases / genetics
  • Cerebellum / abnormalities
  • Cilia / genetics
  • Cilia / metabolism
  • Ciliary Motility Disorders / embryology
  • Ciliary Motility Disorders / genetics
  • Cochlea / cytology
  • Cochlea / embryology*
  • Disease Models, Animal
  • Encephalocele / embryology
  • Encephalocele / genetics
  • Eye Abnormalities / embryology
  • Eye Abnormalities / genetics
  • HEK293 Cells
  • Humans
  • Kidney Diseases, Cystic / embryology
  • Kidney Diseases, Cystic / genetics
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Polycystic Kidney Diseases / embryology
  • Polycystic Kidney Diseases / genetics
  • Retina / abnormalities
  • Retina / cytology
  • Retina / embryology*
  • Retinitis Pigmentosa
  • Wnt Signaling Pathway / physiology
  • Zebrafish / embryology*
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*

Substances

  • Membrane Proteins
  • TMEM67 protein, human
  • TMEM67 protein, mouse
  • Zebrafish Proteins

Supplementary concepts

  • Agenesis of Cerebellar Vermis
  • Meckel syndrome type 1