The pathway of transport of the cystic fibrosis transmembrane regulator (CF
TR) through the early exocytic pathway has not been examined. In contrast t
o most membrane proteins that are concentrated during export from the ER an
d therefore readily detectable at elevated revels in pre-Golgi intermediate
s and Golgi compartments, wild-type CFTR could not be detected in these com
partments using deconvolution immunofluorescence microscopy. To determine t
he basis for this unusual feature, we analyzed CFTR localization using quan
titative immunoelectron microscopy (IEM). We found that wild-type CFTR is p
resent in pre-Golgi compartments and peripheral tubular elements associated
with the cis and trans faces of the Golgi stack, albeit at a concentration
2-fold lower than that found in the endoplasmic reticulum (ER). Delta F508
CFTR, a mutant form that is not efficiently delivered to the cell surface
and the most common mutation in cystic fibrosis, could also be detected at
a reduced concentration in pre-Golgi intermediates and peripheral cis Golgi
elements, but not in post-Golgi compartments. Our results suggest that the
low level of wild-type CFTR in the Golgi region reflects a limiting step i
n selective recruitment by the ER export machinery, an event that is largel
y deficient in Delta F508. We raise the possibility that novel modes of sel
ective anterograde and retrograde traffic between the ER and the Golgi may
serve to regulate CFTR function in the early secretory compartments.