PMC:549712 / 13962-17261 JSONTXT

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Instead, we observed an abundance of mesenchyme that appeared highly immature (Figure 3g). A similar delay in tissue differentiation of Ptdsr -/- embryos was found in the kidneys (Figure 3h). Kidneys from Ptdsr+/+ embryos were well developed at E16.5, showing terminally differentiated glomeruli with Bowman's capsule and collecting tubules lined with cuboidal epithelial cells (Figure 3b). In contrast, Ptdsr-deficient kidneys had only primitive glomeruli at E16.5, and collecting tubules were less well-developed. Instead, a large amount of undifferentiated mesenchyme was present in Ptdsr -/- kidneys (Figure 3h). A delay in tissue differentiation was also found in the intestine at this stage of development. Ptdsr -/- embryos displayed improperly developed villi and an underdeveloped or absent submucosa (Figure 3i). In wild-type embryos (Figure 3c), intestinal cellular differentiation was already highly organized, with intramural ganglion cells between the external and internal muscular layers. Such neuronal cells were absent from the intestine of Ptdsr -/- embryos (Figure 3i), however.\nSome Ptdsr -/- mice (4.5 %) also displayed extensive brain malformations that resulted in externally visible head abnormalities, with occasional ectopic tissue outside the skull or exencephaly (Figure 1f,h). Histological analysis revealed an extensive hyperplasia of brain tissue with herniation of brain tissue either through the skull-cap or through the ventral skull (Figure 3d,j). In the most severe cases, expansion of brain tissue in mutant mice resulted in further perturbations of cortical structures (Figure 3d,j). Of note, a similar brain phenotype was observed in the Ptdsr-deficient mouse line generated by Li and colleagues [31].\nIn contrast to the study of Li et al. [31], however, we found almost normally developed lungs at birth. Ptdsr -/-lungs showed, in comparison to wild-type, only a slight delay in maturation and were fully ventilated in neonates in most cases (Figure 3e,k). This demonstrates that Ptdsr-deficient mice can overcome the delay in embryonic lung differentiation and display normal lung morphology at birth. Thus, it would appear highly unlikely that Ptdsr -/- mice die from respiratory failure. Consistent with the observations of Kunisaki and colleagues [32], we found severely blocked erythropoietic differentiation at an early erythroblast stage in the liver (Figure 3f,3l), suggesting an explanation for the grossly anemic appearance that we observed in our Ptdsr -/- 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