title: Respiratory distress and early neonatal lethality in Hspa4l/Hspa4 double-mutant mice.
abstract: Heat shock proteins HSPA4L and HSPA4 are closely related members of the HSP110 family and act as cochaperones. We generated Hspa4l(-/-)Hspa4(-/-) mice to investigate a functional complementarity between HSPA4L and HSPA4 during embryonic development. Hspa4l(-/-)Hspa4(-/-) embryos exhibited marked pulmonary hypoplasia and neonatal death. Compared with lungs of wild-type, Hspa4l(-/-), and Hspa4(-/-) embryos, Hspa4l(-/-)Hspa4(-/-) lungs were characterized by diminished saccular spaces and increased mesenchymal septa. Mesenchymal hypercellularity was determined to be due to an increased cell proliferation index and decreased cell death. A significant increase in expression levels of prosurvival protein B cell leukemia/lymphoma 2 may be the cause for inhibition of apoptotic process in lungs of Hspa4(-/-)Hspa4l(-/-) embryos. Accumulation of glycogen and diminished expression of surfactant protein B, prosurfactant protein C, and aquaporin 5 in saccular epithelium suggested impaired maturation of type II and type I pneumocytes in the Hspa4l(-/-)Hspa4(-/-) lungs. Further experiments showed a significant accumulation of ubiquitinated proteins in the lungs of Hspa4l(-/-)Hspa4(-/-) embryos, indicating an impaired chaperone activity. Our study demonstrates that HSPA4L and HSPA4 collaborate in embryonic lung maturation, which is necessary for adaptation to air breathing at birth.
authors: 1 Institute of Human Genetics, and.
authors: Belal A
authors: BA
authors: Mohamed
authors: Amal Z
authors: AZ
authors: Barakat
authors: Torsten
authors: T
authors: Held
authors: Manar
authors: M
authors: Elkenani
authors: Christian
authors: C
authors: Mühlfeld
authors: Jörg
authors: J
authors: Männer
authors: Ibrahim M
authors: IM
authors: Adham
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005865:Gestational Age; D050957:HSP110 Heat-Shock Proteins / Q000172:deficiency* / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000172:deficiency* / Q000235:genetics; D008168:Lung / Q000002:abnormalities / Q000378:metabolism* / Q000503:physiopathology; D008171:Lung Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D010641:Phenotype; D012119:Respiration; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D057149:Ubiquitinated Proteins / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D057149:Ubiquitinated Proteins; C485680:Hspa4 protein, mouse; C099678:Hspa4l protein, mouse