Expression and alternative splicing of mouse Gfra4 suggest roles in endocrine cell development

Mol Cell Neurosci. 2000 Jun;15(6):522-33. doi: 10.1006/mcne.2000.0845.


Members of the GDNF protein family signal through receptors consisting of a GPI-linked GFRalpha subunit and the transmembrane tyrosine kinase Ret. Here we characterize the mouse Gfra4 and show that it undergoes developmentally regulated alternative splicing in several tissues. The mammalian GFRalpha4 receptor lacks the first Cys-rich domain characteristic of other GFRalpha receptors. Gfra4 is expressed in many tissues, including nervous system, in which intron retention leads to a putative intracellular or secreted GFRalpha4 protein. Efficient splicing occurs only in thyroid, parathyroid, and pituitary and less in adrenal glands. A splice form that leads to a GPI-linked GFRalpha4 receptor is expressed in juvenile thyroid and parathyroid glands. In newborn and mature thyroid as well as in parathyroid and pituitary glands major transcripts encode for a putative transmembrane isoform of GFRalpha4. Significant loss of thyroid C cells in Ret-deficient mice suggests that C cells and cells in adrenal medulla, which also express Ret, may require signaling via the GFRalpha4-Ret receptor. Finally, in human, GFRalpha4 expression may restrict the inherited cancer syndrome multiple endocrine neoplasia type 2, associated with mutations in RET, to these cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Medulla / metabolism
  • Alternative Splicing / physiology*
  • Animals
  • Cloning, Molecular
  • Cysteine
  • Drosophila Proteins*
  • Exons
  • Gene Expression Regulation, Developmental*
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • In Situ Hybridization
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurosecretory Systems / cytology*
  • Neurosecretory Systems / growth & development
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ret
  • RNA, Messenger / analysis
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction / physiology
  • Thyroid Gland / cytology
  • Thyroid Gland / metabolism


  • Drosophila Proteins
  • Gfra4 protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila
  • Ret protein, mouse
  • Cysteine

Associated data

  • GENBANK/AA823200
  • GENBANK/AF155960
  • GENBANK/AI553572
  • GENBANK/AI845209
  • GENBANK/AJ276514
  • GENBANK/AJ276515
  • GENBANK/AJ276516
  • GENBANK/AJ276870
  • GENBANK/AJ276871
  • GENBANK/AJ276872
  • GENBANK/AU035938