In the adult small intestine, the dynamic renewal of the epithelium is char
acterized by a sequence of cell production in the crypts, cell maturation a
nd cell migration to the tip of villi, where apoptosis is undertaken. Littl
e is known about enterocytic apoptosis during development. In man, intestin
al architectural features and functions are acquired largely by mid-gestati
on (18-20 wks);the question whether the establishment of enterocytic apopto
tic processes parallels or not the acquisition of other intestinal function
al features remains open. In the present study, we approached this question
by examining enterocytic apoptosis during development of the human jejunum
(9-20 wks gestation), using the ISEL (in situ terminal uridine deoxynucleo
tidyl nick-end labelling) method. Between 9 and 17 wks, apoptotic enterocyt
es were not evidenced. However, beginning at the 18 wks stage, ISEL-positiv
e enterocytes were regularly observed at the tip of villi. Since the Bcl-2
family of proteins constitutes a critical checkpoint in apoptosis, acting u
pstream of the apoptotic machinery, we investigated the expression of six B
cl-2 homologs (Bcl-2, Bcl-X-L, Mcl-1, Bax, Bak, Bad) and one non-homologous
associated molecule (Bag-l). By immunofluorescence, we found that all homo
logs analyzed were expressed by enterocytes between 9 and 20 wks. However,
Bcl-2 homologs underwent a gradual compartmentalization of epithelial expre
ssion along the maturing crypt-villus axis, to establish gradients of expre
ssion by 18-20 wks. Western blot analyses indicated that the expression lev
els of Bcl-2 homologs were modulated during morphogenesis of the crypt-vill
us axis, in parallel to their gradual compartmentalization of expression. A
ltogether, these data suggest that regulatory mechanisms of human enterocyt
ic apoptosis become established by mid-gestation (18-20 wks) and coincide w
ith the maturation of the crypt-villus axis of cell proliferation, differen
tiation and renewal.