Integration of Brain and Skull in Prenatal Mouse Models of Apert and Crouzon Syndromes.

Susan M Motch Perrine,Thomas Neuberger,Tim Stecko,Joan T Richtsmeier,Timothy M Ryan,Ethylin W Jabs

doi:10.3389/fnhum.2017.00369

Susan M Motch Perrine, Thomas Neuberger + Show 4 more

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https://doi.org/10.3389/fnhum.2017.00369

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Abstract

The brain and skull represent a complex arrangement of integrated anatomical structures composed of various cell and tissue types that maintain structural and functional association throughout development. Morphological integration, a concept developed in vertebrate morphology and evolutionary biology, describes the coordinated variation of functionally and developmentally related traits of organisms. Syndromic craniosynostosis is characterized by distinctive changes in skull morphology and perceptible, though less well studied, changes in brain structure and morphology. Using mouse models for craniosynostosis conditions, our group has precisely defined how unique craniosynostosis causing mutations in fibroblast growth factor receptors affect brain and skull morphology and dysgenesis involving coordinated tissue-specific effects of these mutations. Here we examine integration of brain and skull in two mouse models for craniosynostosis: one carrying the FGFR2c C342Y mutation associated with Pfeiffer and Crouzon syndromes and a mouse model carrying the FGFR2 S252W mutation, one of two mutations responsible for two-thirds of Apert syndrome cases. Using linear distances estimated from three-dimensional coordinates of landmarks acquired from dual modality imaging of skull (high resolution micro-computed tomography and magnetic resonance microscopy) of mice at embryonic day 17.5, we confirm variation in brain and skull morphology in Fgfr2cC342Y/+ mice, Fgfr2+/S252W mice, and their unaffected littermates. Mutation-specific variation in neural and cranial tissue notwithstanding, patterns of integration of brain and skull differed only subtly between mice carrying either the FGFR2c C342Y or the FGFR2 S252W mutation and their unaffected littermates. However, statistically significant and substantial differences in morphological integration of brain and skull were revealed between the two mutant mouse models, each maintained on a different strain. Relative to the effects of disease-associated mutations, our results reveal a stronger influence of the background genome on patterns of brain-skull integration and suggest robust genetic, developmental, and evolutionary relationships between neural and skeletal tissues of the head.

Highlights

Brain and skull shape track one another closely over evolutionary and developmental time
Morphological Differences of Fgfr2cC342Y/+ and Unaffected Littermates at E17.5 We considered both the relative amount of variation due to skull form and the relative amount of variation attributable to skull shape alone by conducting a principal components analysis (PCA) based on 45 unique inter-landmark distances estimated from 10 neurocranial landmarks (Figures 2B–D; Darroch and Mosimann, 1985; Jungers et al, 1988; Falsetti et al, 1993)
The degree of separation among Fgfr2cC342Y/+ Crouzon syndrome mice and unaffected littermates was similar whether we considered form or shape

Summary

Introduction

Brain and skull shape track one another closely over evolutionary and developmental time. Evidence for the tight morphological correspondence between brain and skull is seen in conditions classified as human diseases of the skull (e.g., craniosynostosis) or of the brain (e.g., holoprosencephaly, microcephaly), even when both tissues are affected. These observations support the idea that the development of the brain and of the skull is guided by tissue-specific genetic factors, but that these tissues respond synchronously to signals (e.g., mechanical forces, mechanically induced cell–cell signaling) generated by growth of neighboring tissues (Richtsmeier and Flaherty, 2013; Lee et al, 2017). Because the sole treatment is surgery, even with appropriate early diagnosis, management of these patients is difficult and individualized care often involves repeated surgeries and life-long psychosocial challenges (Mohr et al, 1978; Fearon et al, 2006; Mehta et al, 2010)

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