Members of the GDNF protein family signal through receptors consisting of a GPI-linked GFR alpha subunit and the transmembrane tyrosine kinase net. Here we characterize the mouse Gfra4 and show that it undergoes developmentally regulated alternative splicing in several tissues. The mammalian GFR alpha 4 receptor lacks the first Cys-rich domain characteristic of other GFR alpha receptors. Gfra4 is expressed in many tissues, including nervous system, in which intron retention leads to a putative intracellular or secreted GFR alpha 4 protein. Efficient splicing occurs only in thyroid, parathyroid, and pituitary and less in adrenal glands. A splice form that leads to a GPI-linked GFRa4 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 GFRa4. Significant loss of thyroid C cells in Ret-deficient mice suggests that c cells and cells in adrenal medulla, which also express Ref, may require signaling via the GFR alpha 4-Ret receptor. Finally, in human, GFR alpha 4 expression may restrict the inherited cancer syndrome multiple endocrine neoplasia type 2, associated with mutations in RET, to these cells.
