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3-Dimensional morphometric analysis of murine bladder development and dysmorphogenesis.

ABSTRACT: Disorders of the urinary tract represent a major cause of morbidity and impaired quality of life. To better understand the morphological events responsible for normal urinary tract development, we performed 3-D reconstructive analysis of developing mouse bladders in control, mgb-/-, and Fgfr2(Mes-/-) mice.Detrusor smooth muscle differentiation initiated in the bladder dome and progressed caudally with the leading edge extending down the right posterior surface of the bladder. Gender-specific differences in detrusor smooth muscle development were observed during early embryonic development. Bladder trigone morphology transitioned from an isosceles to equilateral triangle during development due to the preferential lengthening of the urethra to ureter distance. The primary defect observed in mgb-/- bladders was a significant reduction in detrusor smooth muscle differentiation throughout development. Deviations from normal trigone morphology correlated best with VUR development in Fgfr2(Mes-/-) mice, while alterations in intravesicular tunnel length did not.Multivariate morphometric analysis provides a powerful tool to quantify and assess urinary tract development.

SUBMITTER: Carpenter A

PROVIDER: S-EPMC3288201 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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3-Dimensional morphometric analysis of murine bladder development and dysmorphogenesis.

Carpenter Ashley A Paulus Andrew A Robinson Melissa M Bates Carlton M CM Robinson Michael L ML Hains David D Kline David D McHugh Kirk M KM

Developmental dynamics : an official publication of the American Association of Anatomists 20120131 3

<h4>Background</h4>Disorders of the urinary tract represent a major cause of morbidity and impaired quality of life. To better understand the morphological events responsible for normal urinary tract development, we performed 3-D reconstructive analysis of developing mouse bladders in control, mgb-/-, and Fgfr2(Mes-/-) mice.<h4>Results</h4>Detrusor smooth muscle differentiation initiated in the bladder dome and progressed caudally with the leading edge extending down the right posterior surface ...[more]

PMID: 22275180

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Project description:The Fgfr2c C342Y/+ Crouzon syndrome mouse model carries a cysteine to tyrosine substitution at amino acid position 342 (Cys342Tyr; C342Y) in the fibroblast growth factor receptor 2 (Fgfr2) gene equivalent to a FGFR2 mutation commonly associated with Crouzon and Pfeiffer syndromes in humans. The Fgfr2c C342Y mutation results in constitutive activation of the receptor and is associated with upregulation of osteogenic differentiation. Fgfr2cC342Y/+ Crouzon syndrome mice show premature closure of the coronal suture and other craniofacial anomalies including malocclusion of teeth, most likely due to abnormal craniofacial form. Malformation of the mandible can precipitate a plethora of complications including disrupting development of the upper jaw and palate, impediment of the airway, and alteration of occlusion necessary for proper mastication. The current paradigm of mandibular development assumes that Meckel's cartilage (MC) serves as a support or model for mandibular bone formation and as a template for the later forming mandible. If valid, this implies a functional relationship between MC and the forming mandible, so mandibular dysmorphogenesis might be discerned in MC affecting the relationship between MC and mandibular bone. Here we investigate the relationship of MC to mandible development from the early mineralization of the mandible (E13.5) through the initiation of MC degradation at E17.7 using Fgfr2c C342Y/+ Crouzon syndrome embryos and their unaffected littermates (Fgfr2c +/+ ). Differences between genotypes in both MC and mandibular bone are subtle, however MC of Fgfr2c C342Y/+ embryos is generally longer relative to unaffected littermates at E15.5 with specific aspects remaining relatively large at E17.5. In contrast, mandibular bone is smaller overall in Fgfr2c C342Y/+ embryos relative to their unaffected littermates at E15.5 with the posterior aspect remaining relatively small at E17.5. At a cellular level, differences are identified between genotypes early (E13.5) followed by reduced proliferation in MC (E15.5) and in the forming mandible (E17.5) in Fgfr2c C342Y/+ embryos. Activation of the ERK pathways is reduced in the perichondrium of MC in Fgfr2c C342Y/+ embryos and increased in bone related cells at E15.5. These data reveal that the Fgfr2c C342Y mutation differentially affects cells by type, location, and developmental age indicating a complex set of changes in the cells that make up the lower jaw.

Project description:Recent studies in our lab have identified a mutant mouse model of obstructive nephropathy designated mgb for megabladder. Homozygotic mgb mice (mgb-/-) develop lower urinary tract obstruction in utero due to a lack of bladder smooth muscle differentiation. This defect is the result of a random transgene insertion into chromosome 16 followed by a translocation of this fragment into chromosome 11. In an effort to identify potential gene targets affected in mgb mice, we performed transcriptional profiling on embryonic day 15 (E15) mgb-/- bladders using both a Chromosome 11/16 Custom GeneChip Array and the Affymetrix Mouse Genome 430 2.0 GeneChip. This analysis identified no definitive mis-expressed gene targets on chromosome 11. In contrast, mgb-/- mice significantly over-expressed a cluster of gene products located on the translocated fragment of chromosome 16 including urotensin II-related peptide (Urp), which was shown to be preferentially over-expressed in developing mgb-/- bladders. Immunohistochemical studies indicated that the spatial distribution of Urp was altered in mgb-/- bladders, while biochemical studies suggested a potential role for Urp in modifying smooth muscle cell phenotype in vitro. Pathway analysis of mgb microarray data showed dysregulation of at least 60 gene products associated with the differentiation of smooth muscle. In conclusion, the results of this study indicate that the molecular pathways controlling normal smooth muscle development are severely altered in mgb-/- bladders, and provide the first evidence that Urp may play a critical role in bladder smooth muscle development. Keywords: mgb mutant bladders Gene expression profiling was performed on two separate study groups. First, total cellular RNA was isolated from wildtype (n=2; 1 female/1 male), mgb+/- (n=2; 1 female/1 male), and mgb-/- (n=2; 1 female/1 male) E15 whole embryos. Second, total cellular RNA was isolated from the bladders of E15 wildtype (n=7; 3 female/4 male), mgb+/- mice (n=7; 3 female/4 male), and mgb-/- mice (n=11; 7 females/4 males).

Dataset Information

3-Dimensional morphometric analysis of murine bladder development and dysmorphogenesis.

Publications

3-Dimensional morphometric analysis of murine bladder development and dysmorphogenesis.

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