Читать книгу Pathology of Genetically Engineered and Other Mutant Mice - Группа авторов - Страница 98

Young mice that develop hydrocephalus before their cranial sutures close typically present with an enlarged, domed head (Figure 6.2), but the majority of cases have milder disease that may not be evident until the head is sectioned. Hydrocephalus may be caused by a blockage of the normal flow of cerebrospinal fluid (CSF), a failure of absorption of CSF, or least commonly, an overproduction of CSF. Although there are many different potential causes of hydrocephalus, a motile ciliopathy is most likely involved when the brain lesion is accompanied by rhinosinusitis, defective spermatozoa, or laterality defects. Abnormal or deficient motility of ependymal cilia during brain morphogenesis clearly contributes to the development of hydrocephalus in many mice [28]. The synchronous beat of ependymal cilia that line the ventricles and interventricular connections generates a directional flow of CSF which has been termed “ependymal flow” [29], which may be required to maintain the patency of the aqueduct. The absence of ependymal flow during early postnatal brain development has been linked to secondary aqueduct stenosis [29].

However, congenital hydrocephalus in mice is a complex polygenic trait, and its development is strongly influenced by the presence of strain‐specific genetic modifiers. For example, hydrocephalus is a relatively common finding in C57BL/6 mice, and it has been observed that Del(1)Brk (formerly nm1054) [30] and Fyn‐deficient mice on C57BL/6 backgrounds develop severe hydrocephalus, while mutants on 129 or mixed background showed either mild or no hydrocephalus [30, 31]. Similarly, hydrocephalus develops in L1‐deficient mice only after backcrossing to the C57BL/6 strain, with the mutation eventually becoming embryonic lethal after several backcrosses [32]. Taken together, these findings suggest that C57BL/6 already carry mutant alleles that predispose them to having dysfunctional motile cilia and thus to developing hydrocephalus and other motile ciliopathies. Although most cases of hydrocephalus can be linked to dysfunctional motile cilia, it is clear that primary cilia are involved in cellular signal pathways expressed during early brain development that can result in hydrocephalus when disrupted. The previously described L1‐deficient mutant mice develop severe hydrocephalus that does not involve either aqueduct stenosis or ultrastructural abnormalities of ependymal cells or cilia lining the lateral ventricles or the aqueduct [33].

Figure 6.2 Brain hydrocephalus. Ependymal ciliary dysfunction often results in severe dilatation of the ventricles in the brain.