title: Mucolipin co-deficiency causes accelerated endolysosomal vacuolation of enterocytes and failure-to-thrive from birth to weaning.
abstract: During the suckling period, intestinal enterocytes are richly endowed with endosomes and lysosomes, which they presumably utilize for the uptake and intracellular digestion of milk proteins. By weaning, mature intestinal enterocytes replace those rich in lysosomes. We found that mouse enterocytes before weaning express high levels of two endolysosomal cation channels, mucolipins 3 and 1 -products of Trpml3 and Trpml1 genes; moreover neonatal enterocytes of mice lacking both mucolipins (Trpml3-/-;Trpml1-/-) vacuolated pathologically within hours of birth and remained so until weaning. Ultrastructurally and chemically these fast-forming vacuoles resembled those that systemically appear in epithelial cells of mucolipidosis type IV (MLIV) patients, which bear mutations in Trpml1. Hence, lack of both mucolipins 1 and 3 causes an accelerated MLIV-type of vacuolation in enterocytes. The vacuoles were aberrant hybrid organelles with both endosomal and lysosomal components, and were not generated by alterations in endocytosis or exocytosis, but likely by an imbalance between fusion of lysosomes and endosomes and their subsequent scission. However, upon extensive vacuolation enterocytes displayed reduced endocytosis from the intestinal lumen, a defect expected to compromise nutrient uptake. Mice lacking both mucolipins suffered a growth delay that began after birth and continued through the suckling period but recovered after weaning, coinciding with the developmental period of enterocyte vacuolation. Our results demonstrate genetic redundancy between lysosomal mucolipins 3 and 1 in neonatal enterocytes. Furthermore, our Trpml3-/-;Trpml1-/- mice represent a polygenic animal model of the poorly-understood, and often intractable, neonatal failure-to-thrive with intestinal pathology. Our results implicate lysosomes in neonatal intestinal pathologies, a major cause of infant mortality worldwide, and suggest transient intestinal dysfunction might affect newborns with lysosomal storage disorders. Finally, we conclude that mucolipin-endowed lysosomes in the young play an evolutionarily-conserved role in the intracellular digestion of maternally-provided nutrients, whether milk in mammals or yolk in oviparous species.
authors.affiliation: Driskill Graduate Program in the Life Sciences (DGP), Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Natalie N
authors.initials: NN
authors.lastname: Remis
authors.affiliation: Driskill Graduate Program in the Life Sciences (DGP), Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Teerawat
authors.initials: T
authors.lastname: Wiwatpanit
authors.affiliation: Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Castiglioni
authors.affiliation: Northwestern University Interdepartmental Neuroscience (NUIN) graduate program, Chicago, Illinois, United States of America.
authors.forename: Emma N
authors.initials: EN
authors.lastname: Flores
authors.affiliation: Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Cantú
authors.affiliation: Driskill Graduate Program in the Life Sciences (DGP), Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America; Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America; Northwestern University Interdepartmental Neuroscience (NUIN) graduate program, Chicago, Illinois, United States of America; Departments of Neurology and Physiology, and Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Jaime
authors.initials: J
authors.lastname: García-Añoveros
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D004195:Disease Models, Animal; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D020895:Enterocytes / Q000378:metabolism*; D004847:Epithelial Cells; D019143:Evolution, Molecular; D005089:Exocytosis; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008892:Milk; D050051:Transient Receptor Potential Channels / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D014617:Vacuoles / Q000378:metabolism; D014886:Weaning
chemical_list: C512321:Mcoln1 protein, mouse; C470193:Mcoln3 protein, mouse; D050051:Transient Receptor Potential Channels