Postnatal brain and skull growth in an Apert syndrome mouse model

Abstract

Craniofacial and neural tissues develop in concert throughout pre- and postnatal growth. FGFR-related craniosynostosis syndromes, such as Apert syndrome (AS), are associated with specific phenotypes involving both the skull and the brain. We analyzed the effects of the FGFR P253R mutation for Apert syndrome using the Fgfr2+/P253R mouse to evaluate the effects of this mutation on these two tissues over the course of development from day of birth (P0) to postnatal day 2 (P2). Three-dimensional magnetic resonance microscopy and computed tomography images were acquired from Fgfr2+/P253R mice and unaffected littermates at P0 (N=28) and P2 (N=23). 3D coordinate data for 23 skull and 15 brain landmarks were statistically compared between groups. Results demonstrate that the Fgfr2+/P253R mice show reduced growth in the facial skeleton and the cerebrum, while the height and width of the neurocranium and caudal regions of the brain show increased growth relative to unaffected littermates. This localized correspondence of differential growth patterns in skull and brain point to their continued interaction through development and suggest that both tissues display divergent postnatal growth patterns relative to unaffected littermates. However, the change in the skull-brain relationship from P0 to P2 implies that each tissue affected by the mutation retains a degree of independence, rather than one tissue directing the development of the other.

Prenatal development of skull and brain in a mouse model of growth restriction

“…Evidence of semi-autonomous changes in the brain and skull is also provided by mutant mice. Models for Apert syndrome, for example, show that both structures display a relative dissociation in their size at early postnatal stages, which is interpreted in terms of stronger effects of the mutation on the skull than on the brain PRENATAL DEVELOPMENT OF SKULL AND BRAIN (Hill et al, 2013). According to our results, the environmental perturbation induced here has a similar effect on prenatally growing brain and skull size, showing the generalized effect of maternal malnutrition on these tissues.…”

“…After studying a model for craniosynostosis, Aldridge et al (2010) concluded that the processes underlying alterations of the vault are relatively independent from those causing brain dysmorphologies. Hill et al (2013) also found a non-significant correlation between brain and skull morphology in mice at the time of birth, which is an ontogenetic stage very close to the late prenatal day analyzed in our study. However, they noted that this trend is altered in the immediately following days and two days after birth, when skull and brain morphology correlate significantly.…”

“…For the case of the mammalian skull, mice represent the most widely studied model. So far, the work on this topic has focused on the effect of genetic mutations related to noticeable dysmorphologies, such as craniosynostosis and altered brain growth (Aldridge et al, 2005a(Aldridge et al, , b, 2010, and on the analysis of very early prenatal (Boughner et al, 2008;Marcucio et al, 2011) and postnatal stages (Hill et al, 2013).…”

Closing the Gap: Genetic and Genomic Continuum from Syndromic to Nonsyndromic Craniosynostoses

“…In animal models for human craniosynostosis syndromes, the abnormal skull shape can be detected before the premature closure of cranial vault sutures 71•, 72•]. The development of animal models for craniosynostosis [70, 73, 74] has already revealed many molecularly driven three-dimensional morphological changes in soft tissues of the head and skull that were not apparent in humans [71•, 75, 76•, 77]. These changes are more difficult to evaluate quantitatively in humans where observations are routinely made postnatally and there is a lack of appropriate morphological control data sets to make meaningful comparisons to abnormal phenotypes.…”

Infantile hydrocephalus: A review of epidemiology, classification and causes

“…In these conditions, mutations in fibroblast growth factor receptor (FGFR) genes cause cranial changes that obstruct flow of CSF and reduce absorption into the systemic circulation by increasing venous pressure [72, 73]. Mutations in these genes can also cause excessive growth of the brain itself, thereby compounding the problem [74-77]. Interestingly, hydrocephalus can accompany FGFR-associated skeletal dysplasias as well, likely reflecting the same underlying mechansims.…”