Novel mouse model of encephalocele: post-neurulation origin and relationship to open neural tube defects

Abstract

Corresponding authors: a.copp@ucl.ac.uk and anarolo@hotmail.com Running title: Novel mouse model of encephalocele 2 SUMMARY STATEMENT Encephalocele -a severe brain defect -arises after neural tube closure, but can share a common genetic cause with anencephaly, a defect of neural tube closure. ABSTRACT Encephalocele is a clinically important birth defect that can lead to severe disability in childhood and beyond. The embryonic pathogenesis of encephalocele is poorly understood and, while 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, non-syndromic 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 large proportion of mutant fetuses exhibit encephalocele affecting the occipito-parietal region. The encephalocele phenotype does not result from a defect in 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 down-regulation of Rac1 and appears morphologically normal until late gestation. A large skull defect develops overlying the region of brain herniation. Our work provides a new genetic model of occipitoparietal encephalocele, particularly resembling non-syndromic human cases. While encephalocele has a different, later-arising pathogenesis than open neural tube defects, both can share the same genetic causation.

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

“…Knockdown of the cell migration molecule Itgb1 prevents closure of the neuropore 47 . Mice with ablation of Rac1, a molecule modulating actin cytoskeleton remodeling and cell migration in NNE, developed open spina bifida, exencephaly or anencephaly 48 . In addition, impaired mesodermal cell migration due to diabetic pregnancy led to NTDs in mouse 49 .…”

Influenza as a Measure of Maternal Immune Activation and Its Effects on the Incidence of Encephalocele and Microtia

“…Current research on encephalocele development describes a timeline different from those of other neural tube defects such as spina bifida and anencephaly. 26 Supporting this difference in pathogenesis is the observation that elevated maternal blood alpha fetoprotein during early second trimester in fetal spina bifida but not frontal encephalocele. 27 In fact, it has now been called into question if frontal encephalocele results from defective neural tube closure, rather it is a “post-neurulation” defect.…”

From Neural Crest to Definitive Roof Plate: The Dynamic Behavior of the Dorsal Neural Tube

“…The development of the dorsal NT embodies basic processes in development: the regulation of cell proliferation, cellular movements and cell elongation, epithelial-mesenchymal transitions, lineage decisions, and relationships between them. Aberrant signaling during critical phases leads to disease, ranging from defects in NT closure [ 142 , 143 , 144 ], lack of dorsal cell types [ 50 , 92 , 133 ], neurocristopathies [ 145 , 146 ], and tumors generated from RP derivatives such as choroid plexus papillomas or carcinomas [ 147 ]. Our expanding knowledge of basic mechanisms of development should assist us in developing animal models for addressing their etiology, prevention and treatment.…”