The ubiquitin ligase Mindbomb 1 coordinates gastrointestinal secretory cell maturation
Benjamin J. Capoccia, Ramon U. Jin, Young-Yun Kong, Richard M. Peek Jr., Matteo Fassan, Massimo Rugge, Jason C. Mills
Benjamin J. Capoccia, Ramon U. Jin, Young-Yun Kong, Richard M. Peek Jr., Matteo Fassan, Massimo Rugge, Jason C. Mills
View: Text | PDF
Research Article Gastroenterology

The ubiquitin ligase Mindbomb 1 coordinates gastrointestinal secretory cell maturation

Abstract

After cell fate specification, differentiating cells must amplify the specific subcellular features required for their specialized function. How cells regulate such subcellular scaling is a fundamental unanswered question. Here, we show that the E3 ubiquitin ligase Mindbomb 1 (MIB1) is required for the apical secretory apparatus established by gastric zymogenic cells as they differentiate from their progenitors. When Mib1 was deleted, death-associated protein kinase–1 (DAPK1) was rerouted to the cell base, microtubule-associated protein 1B (MAP1B) was dephosphorylated, and the apical vesicles that normally support mature secretory granules were dispersed. Consequently, secretory granules did not mature. The transcription factor MIST1 bound the first intron of Mib1 and regulated its expression. We further showed that loss of MIB1 and dismantling of the apical secretory apparatus was the earliest quantifiable aberration in zymogenic cells undergoing transition to a precancerous metaplastic state in mouse and human stomach. Our results reveal a mechanistic pathway by which cells can scale up a specific, specialized subcellular compartment to alter function during differentiation and scale it down during disease.

Authors

Benjamin J. Capoccia, Ramon U. Jin, Young-Yun Kong, Richard M. Peek Jr., Matteo Fassan, Massimo Rugge, Jason C. Mills

×

Figure 1

Microtubules and MAP1B coordinate apical compartment expansion and endolysosomal trafficking in gastric ZCs.

Options: View larger image (or click on image) Download as PowerPoint
Microtubules and MAP1B coordinate apical compartment expansion and endol...
(A) Morphological changes that take place as neck cells secreting mucus (small white granules) differentiate into ZCs secreting zymogen (large black granules). The cells are oriented with the gastric lumen at the top and the basement membrane at the bottom. Arrows indicate vectors of expansion or contraction during the maturation process. (B) Representative section of the base zone of the gastric unit (thick dashed outline) stained for anti–α-tubulin (green) antibodies and Hoechst (blue, nuclei; thin dashed or solid outlines). A single ZC is highlighted (solid outline). (C) Fluorescent microscopy of the neck, transition (TZ), and base zones of the gastric unit from wild-type mice stained with antibodies against GSII (red, neck cells) and CI-M6PR (green; left) and cathepsin L (green; right). Neck cells and ZCs (solid outline) are shown enlarged in the insets. Expression of CI-M6PR and cathepsin L in transitional cells and parietal cells is indicated by arrowheads and arrows, respectively. (D) Fluorescent microscopy of gastric unit from wild-type mice stained with GSII (magenta, neck cells), anti–α-tubulin (green), and anti-MAP1B (red). Enlarged views of individual neck cell, parietal cell, and ZC stained with α-tubulin and MAP1B, as well as merged images, are shown in the insets. Scale bars: 5 μm (B; C and D, insets), 10 μm (C and D).