DEVELOPMENTAL EXPRESSION OF A MUCINLIKE GLYCOPROTEIN (MUCLIN) IN PANCREAS AND SMALL-INTESTINE OF CF MICE

The mucinlike glycoprotein MUCLIN, one of two protein products of the CRP-ductin gene, was used to study changes in the expression of sulfat ed glycoconjugates during the pathogenesis of cystic fibrosis, using t he cystic fibrosis transmembrane conductance regulator (CFTR) knockout mouse (CF mouse). We assessed the appearance of dilated lumina contai ning protein or mucus plugs in pancreatic acini and crypts of the smal l intestine and quantified MUCLIN protein and CRP-ductin mRNA during p ostnatal development. In CF mice, the pancreatic acinar lumen was dila ted by postnatal day 16 (P16), but MUCLIN protein was first significan tly increased by P23 and remained elevated through adulthood compared with normal mice. Similarly, intestinal crypts had CF-like mucus plugs by P16, but MUCLIN protein was first elevated by P23 and remained ele vated through adulthood compared with normal mice. In both organs, MUC LIN labeling of the luminal surface was increased concomitantly with d ilation and protein or mucus plugging but before upregulation of expre ssion. The morphological changes were then followed by upregulation of MUCLIN protein and CRP-ductin mRNA expression. This is the first dire ct study of CF pathogenesis and the resultant increase in glycoconjuga te gene expression. The data are consistent with CF pathogenesis progr essing from an initial alteration in protein secretory dynamics (incre ased luminal MUCLIN and protein/mucus plugs) to an upregulation of gly coprotein/mucin gene expression, which is expected to exacerbate obstr uction of the luminal spaces.