title: Loss of MYO5B in mice recapitulates Microvillus Inclusion Disease and reveals an apical trafficking pathway distinct to neonatal duodenum.
abstract: Inactivating mutations in MYO5B cause severe neonatal diarrhea in Microvillus Inclusion Disease. Loss of active MYO5B causes the formation of pathognomonic inclusions and aberrations in brush border enzymes.
  
  
  
  We developed three mouse models of germline, constitutively intestinal targeted and inducible intestinal targeted deletion of MYO5B. The mice were evaluated for enterocyte cellular morphology.
  
  
  
  Germline MYO5B KO mice showed early diarrhea and failure to thrive with evident microvillus inclusions and loss of apical transporters in the duodenum. IgG was present within inclusions. Apical transporters were lost and inclusions were present in the duodenum, but were nearly absent in the ileum. VillinCre;MYO5BF/Fmice showed similar pathology and morphological changes in duodenal enterocytes. In contrast, when MYO5B KO was induced with tamoxifen treatment at 8 weeks of age, VillinCreERT2;MYO5BF/Fmice developed severe diarrhea with loss of duodenal brush border enzymes, but few inclusions were observed in enterocytes. However, if tamoxifen is administered to 2-day-old VillinCreERT2;MYO5BF/Fmice, prominent microvillus inclusions were observed.
  
  
  
  The microvillus inclusions that develop after MYO5B loss reveal the presence of an unrecognized apical membrane trafficking pathway in neonatal duodenal enterocytes. However, the diarrheal pathology after MYO5B loss is due to deficits in transporter presentation at the apical membrane in duodenal enterocytes.
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Victoria G
authors.initials: VG
authors.lastname: Weis
authors.affiliation: Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Byron C
authors.initials: BC
authors.lastname: Knowles
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA; Nashville VA Medical Center, Nashville, TN, USA.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Choi
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Goldstein
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Williams
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA; Nashville VA Medical Center, Nashville, TN, USA.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Manning
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Roland
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA; Nashville VA Medical Center, Nashville, TN, USA.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Lapierre
authors.affiliation: Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA; Nashville VA Medical Center, Nashville, TN, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Goldenring
keywords: Enterocyte trafficking; NHE3; Rab11a; Rab8a; Syntaxin 3; brush border