Abstract
ABSTRACTEncephalocele is a clinically important birth defect that can lead to severe disability in childhood and beyond. The embryonic and early fetal pathogenesis of encephalocele is poorly understood and, although usually classified as a ‘neural tube defect’, there is conflicting evidence on whether encephalocele results from defective neural tube closure or is a post-neurulation defect. It is also unclear whether encephalocele can result from the same causative factors as anencephaly and open spina bifida, or whether it is aetiologically distinct. This lack of information results largely from the scarce availability of animal models of encephalocele, particularly ones that resemble the commonest, nonsyndromic human defects. Here, we report a novel mouse model of occipito-parietal encephalocele, in which the small GTPase Rac1 is conditionally ablated in the (non-neural) surface ectoderm. Most mutant fetuses have open spina bifida, and some also exhibit exencephaly/anencephaly. However, a proportion of mutant fetuses exhibit brain herniation, affecting the occipito-parietal region and closely resembling encephalocele. The encephalocele phenotype does not result from defective neural tube closure, but rather from a later disruption of the surface ectoderm covering the already closed neural tube, allowing the brain to herniate. The neuroepithelium itself shows no downregulation of Rac1 and appears morphologically normal until late gestation. A large skull defect overlies the region of brain herniation. Our work provides a new genetic model of occipito-parietal encephalocele, particularly resembling nonsyndromic human cases. Although encephalocele has a different, later-arising pathogenesis than open neural tube defects, both can share the same genetic causation.
Highlights
Encephalocele is a severe birth defect of the skull and brain, with a median prevalence of 0.1-0.3 per 1000 births, but with considerable geographical variation in frequency (Zaganjor et al, 2016)
A dorsally curled tail can result from delayed spinal neural tube closure (Copp, 1985), indicating that overall more than 90% of Grhl3-Rac1 mutant fetuses exhibit delayed or failed spinal closure
Defective closure of the neural tube and abdominal wall, and brain herniation, all co-exist in the mouse model, prompting the question: does the same Rac1-related pathogenic mechanism apply in each case? We found evidence of surface ectoderm rupture, preceding brain herniation in fetuses with encephalocele
Summary
Encephalocele is a severe birth defect of the skull and brain, with a median prevalence of 0.1-0.3 per 1000 births, but with considerable geographical variation in frequency (Zaganjor et al, 2016). Encephaloceles emerge along the skull midline, with variation in rostro-caudal location which can be fronto-ethmoidal, parietal, occipital or cervical. The prognosis worsens with posterior location, size of sac and increasing amount of herniated brain tissue (Kiymaz et al, 2010). Occipital encephalocele is best known as part of Meckel syndrome (overlapping with Joubert syndrome), in which individuals exhibit polydactyly, polycystic kidneys and biliary defects. Mutations in several genes (e.g. MKS1, MKS2 (TMEM216), MKS3 (TMEM67), CEP290, RPGRIP1L) have been identified in various forms of Meckel syndrome (Logan et al, 2010). Cellular analysis of the MKS proteins has demonstrated a key role in the structure and function of primary cilia, and Meckel syndrome is classified as a ciliopathy
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