Abstract
BackgroundIncreased apposition of the frontal and parietal bones of the skull during embryogenesis may be a risk factor for the subsequent development of premature skull fusion, or craniosynostosis. Human craniosynostosis is a prevalent, and often serious embryological and neonatal pathology. Other than known mutations in a small number of contributing genes, the aetiology of craniosynostosis is largely unknown. Therefore, the identification of novel genes which contribute to normal skull patterning, morphology and premature suture apposition is imperative, in order to fully understand the genetic regulation of cranial development.ResultsUsing advanced imaging techniques and quantitative measurement, we show that genetic deletion of the highly-conserved transcription factor Grainyhead-like 3 (Grhl3) in mice (Grhl3 −/−) leads to decreased skull size, aberrant skull morphology and premature apposition of the coronal sutures during embryogenesis. Furthermore, Grhl3 −/− mice also present with premature collagen deposition and osteoblast alignment at the sutures, and the physical interaction between the developing skull, and outermost covering of the brain (the dura mater), as well as the overlying dermis and subcutaneous tissue, appears compromised in embryos lacking Grhl3. Although Grhl3 −/− mice die at birth, we investigated skull morphology and size in adult animals lacking one Grhl3 allele (heterozygous; Grhl3 +/−), which are viable and fertile. We found that these adult mice also present with a smaller cranial cavity, suggestive of post-natal haploinsufficiency in the context of cranial development.ConclusionsOur findings show that our Grhl3 mice present with increased apposition of the frontal and parietal bones, suggesting that Grhl3 may be involved in the developmental pathogenesis of craniosynostosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-016-0136-7) contains supplementary material, which is available to authorized users.
Highlights
Increased apposition of the frontal and parietal bones of the skull during embryogenesis may be a risk factor for the subsequent development of premature skull fusion, or craniosynostosis
Having dissected the caudal half of the skull from the cranial half to allow clear views of the coronal suture from above we could demonstrate a clear boundary of non-calcified tissue between the frontal and parietal embryos in lateral (e, f) and dorsal (g, h) views, highlighting skull morphology and suture development. i, j High-powered images of the boxed region in (g, h), showing a clearly open suture in WT embryos (i), and a fused suture in Grainyhead-like 3 (Grhl3)−/− embryos (j) bones in the WT, while this was qualitatively less appreciable in the Grhl3−/− (Fig. 1g, h)
Coronal craniosynostosis in humans presents with a spectrum of severity and its aetiology is multifactorial outside a narrow set of syndromes
Summary
Increased apposition of the frontal and parietal bones of the skull during embryogenesis may be a risk factor for the subsequent development of premature skull fusion, or craniosynostosis. The identification of novel genes which contribute to normal skull patterning, morphology and premature suture apposition is imperative, in order to fully understand the genetic regulation of cranial development. Increased apposition of developing bones in the skull is an early event in the aetiology of craniosynostosis, the pathological condition whereby cranial sutures fuse prematurely. This may produce a spectrum of congenital deformities of the skull, and brain, and is estimated to affect 1:2,000–1:2,500 live births [1–3]. The aetiology of most non syndromic cases remains uncertain, but genetic mutations and epigenetic factors, including maternal drugs and diet are recognized [4]
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