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

Members of the GDNF protein family signal through receptors consisting of a GPI-linked GFR alpha subunit and the transmembrane tyrosine kinase net. He re we characterize the mouse Gfra4 and show that it undergoes developmental ly regulated alternative splicing in several tissues. The mammalian GFR alp ha 4 receptor lacks the first Cys-rich domain characteristic of other GFR a lpha receptors. Gfra4 is expressed in many tissues, including nervous syste m, 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 G PI-linked GFRa4 receptor is expressed in juvenile thyroid and parathyroid g lands. In newborn and mature thyroid as well as in parathyroid and pituitar y glands major transcripts encode for a putative transmembrane isoform of G FRa4. Significant loss of thyroid C cells in Ret-deficient mice suggests th at c cells and cells in adrenal medulla, which also express Ref, may requir e 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.