Yap is required for ependymal integrity and is suppressed in LPA-induced hydrocephalus.
Ontology highlight
ABSTRACT:
SUBMITTER: Park R
PROVIDER: S-EPMC4729961 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Hydrocephalus is a common congenital anomaly. LCAM1 and MPDZ (MUPP1) are the only known human gene loci associated with non-syndromic hydrocephalus. To investigate functions of the tight junction-associated protein Mpdz, we generated mouse models. Global Mpdz gene deletion or conditional inactivation in Nestin-positive cells led to formation of supratentorial hydrocephalus in the early postnatal period. Blood vessels, epithelial cells of the choroid plexus, and cilia on ependymal cells, which line the ventricular system, remained morphologically intact in Mpdz-deficient brains. However, flow of cerebrospinal fluid through the cerebral aqueduct was blocked from postnatal day 3 onward. Silencing of Mpdz expression in cultured epithelial cells impaired barrier integrity, and loss of Mpdz in astrocytes increased RhoA activity. In Mpdz-deficient mice, ependymal cells had morphologically normal tight junctions, but expression of the interacting planar cell polarity protein Pals1 was diminished and barrier integrity got progressively lost. Ependymal denudation was accompanied by reactive astrogliosis leading to aqueductal stenosis. This work provides a relevant hydrocephalus mouse model and demonstrates that Mpdz is essential to maintain integrity of the ependyma.
| S-EPMC5494508 | biostudies-literature
Project description:Heterozygous mutations affecting FOXJ1, a transcription factor governing multiciliated cell development, have been associated with obstructive hydrocephalus in humans. However, factors that disrupt multiciliated ependymal cell function often cause communicating hydrocephalus, raising questions about whether FOXJ1 mutations cause hydrocephalus primarily by blocking cerebrospinal fluid (CSF) flow or by different mechanisms. Here, we show that heterozygous FOXJ1 mutations are also associated with communicating hydrocephalus in humans and cause communicating hydrocephalus in mice. Disruption of one Foxj1 allele in mice leads to incomplete ependymal cell differentiation and communicating hydrocephalus. Mature ependymal cell number and motile cilia number are decreased, and 12% of motile cilia display abnormal axonemes. We observed decreased microtubule attachment to basal bodies, random localization and orientation of basal body patches, loss of planar cell polarity, and a disruption of unidirectional CSF flow. Thus, heterozygous FOXJ1 mutations impair ventricular multiciliated cell differentiation, thereby causing communicating hydrocephalus. CSF flow obstruction may develop secondarily in some patients harboring FOXJ1 mutations. Heterozygous FOXJ1 mutations impair motile cilia structure and basal body alignment, thereby disrupting CSF flow dynamics and causing communicating hydrocephalus.
| S-EPMC10661798 | biostudies-literature
Project description:Hydrocephalus is a common neurological condition, characterized by the excessive accumulation of cerebrospinal fluid in the cerebral ventricles. Primary treatments for hydrocephalus mainly involve neurosurgical cerebrospinal fluid diversion, which hold high morbidity and failure rates, highlighting the necessity for the discovery of novel therapeutic approaches. Although the pathophysiology of hydrocephalus is highly multifactorial, impaired function of the brain ependymal cells plays a fundamental role in hydrocephalus. Here we show that GemC1 and McIdas, key regulators of multiciliated ependymal cell fate determination, induce direct cellular reprogramming towards ependyma. Our study reveals that ectopic expression of GemC1 and McIdas reprograms cortical astrocytes and programs mouse embryonic stem cells into ependyma. McIdas is sufficient to establish functional activity in the reprogrammed astrocytes. Furthermore, we show that McIdas' expression promotes ependymal cells regeneration in two different postnatal hydrocephalus mouse models: an intracranial hemorrhage and a genetic form of hydrocephalus and ameliorates the cytoarchitecture of the neurogenic niche. Our study provides evidence on the restoration of ependyma in animal models mimicking hydrocephalus that could be exploited towards future therapeutic interventions.
| S-SCDT-10_1038-S44321-024-00156-5 | biostudies-other
Project description:Hydrocephalus is characterized by abnormal accumulation of cerebrospinal fluid (CSF) in the ventricular cavity. The circulation of CSF in brain ventricles is controlled by the coordinated beating of motile cilia at the surface of ependymal cells (ECs). Here, we show that MT1-MMP is highly expressed in olfactory bulb, rostral migratory stream, and the ventricular system. Mice deficient for membrane-type 1-MMP (MT1-MMP) developed typical phenotypes observed in hydrocephalus, such as dome-shaped skulls, dilated ventricles, corpus callosum agenesis, and astrocyte hypertrophy, during the first 2 weeks of postnatal development. MT1-MMP-deficient mice exhibited reduced and disorganized motile cilia with the impaired maturation of ECs, leading to abnormal CSF flow. Consistent with the defects in motile cilia morphogenesis, the expression of promulticiliogenic genes was significantly decreased, with a concomitant hyperactivation of Notch signaling in the walls of lateral ventricles in Mmp14-/- brains. Inhibition of Notch signaling by ?-secretase inhibitor restored ciliogenesis in Mmp14-/- ECs. Taken together, these data suggest that MT1-MMP is required for ciliogenesis and EC maturation through suppression of Notch signaling during early brain development. Our findings indicate that MT1-MMP is critical for early brain development and loss of MT1-MMP activity gives rise to hydrocephalus.
| S-EPMC7253023 | biostudies-literature
Project description:Posthemorrhagic hydrocephalus (PHH) in premature infants is a common neurological disorder treated with invasive neurosurgical interventions. Patients with PHH lack effective therapeutic interventions and suffer chronic comorbidities. Here, we report a murine lysophosphatidic acid (LPA)-induced postnatal PHH model that maps neurodevelopmentally to premature infants, a clinically accessible high-risk population, and demonstrates ventriculomegaly with increased intracranial pressure. Administration of LPA, a blood-borne signaling lipid, acutely disrupted the ependymal cells that generate CSF flow, which was followed by cell death, phagocytosis, and ventricular surface denudation. This mechanism is distinct from a previously reported fetal model that induces PHH through developmental alterations. Analyses of LPA receptor-null mice identified LPA1 and LPA3 as key mediators of PHH. Pharmacological blockade of LPA1 prevented PHH in LPA-injected animals, supporting the medical tractability of LPA receptor antagonists in preventing PHH and negative CNS sequelae in premature infants.
| S-EPMC6785248 | biostudies-literature
Project description:Multiciliated ependymal cells line the ventricle wall and generate CSF flow through ciliary beating. Defects in ependymal cells cause hydrocephalus; however, there are still significant gaps in our understanding the molecular, cellular and developmental mechanisms involved in the pathogenesis of hydrocephalus. Here, we demonstrate that specific deletion of RNA-binding protein (RBP) Hu antigen R (HuR) in the mouse brain results in hydrocephalus and causes postnatal death. HuR deficiency leads to impaired ependymal cell development with defective motile ciliogenesis in both female and male mice. Transcriptome-wide analysis reveals that HuR binds to mRNA transcripts related to ciliogenesis, including cilia and flagella associated protein 52 (Cfap52), the effector gene of Foxj-1 and Rfx transcriptional factors. HuR deficiency accelerates the degradation of Cfap52 mRNA, while overexpression of Cfap52 is able to promote the development of HuR-deficient ependymal cells. Taken together, our results unravel the important role of HuR in posttranscriptional regulation of ependymal cell development by stabilizing Cfap52 mRNA.SIGNIFICANCE STATEMENT This study identifies Hu antigen R (HuR) as a genetic factor involved in the pathogenesis of hydrocephalus. Mechanistically, HuR regulates ependymal cell differentiation and ciliogenesis through stabilizing Cfap52 mRNA, the effector gene of Foxj-1 and Rfx transcriptional factors.
| S-EPMC8802941 | biostudies-literature
Project description:Ependymal cells are part of the neurogenic niche in the adult subventricular zone of the lateral ventricles, where they regulate neurogenesis and neuroblast migration. Ependymal cells are generated from radial glia cells during embryonic brain development and acquire their final characteristics postnatally. The homeobox gene Six3 is expressed in ependymal cells during the formation of the lateral wall of the lateral ventricles in the brain. Here, we show that Six3 is necessary for ependymal cell maturation during postnatal stages of brain development. In its absence, ependymal cells fail to suppress radial glia characteristics, resulting in a defective lateral wall, abnormal neuroblast migration and differentiation, and hydrocephaly.
| S-EPMC3222208 | biostudies-literature
Project description:Defects in ependymal (E) cells, which line the ventricle and generate cerebrospinal fluid flow through ciliary beating, can cause hydrocephalus. Dishevelled genes (Dvls) are essential for Wnt signaling, and Dvl2 has been shown to localize to the rootlet of motile cilia. Using the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mouse, we show that compound genetic ablation of Dvls causes hydrocephalus. In hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mutants, E cells differentiated normally, but the intracellular and intercellular rotational alignments of ependymal motile cilia were disrupted. As a consequence, the fluid flow generated by the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) E cells was significantly slower than that observed in control mice. Dvls were also required for the proper positioning of motile cilia on the apical surface. Tamoxifen-induced conditional removal of Dvls in adult mice also resulted in defects in intracellular rotational alignment and positioning of ependymal motile cilia. These results suggest that Dvls are continuously required for E cell planar polarity and may prevent hydrocephalus.
| S-EPMC4126882 | biostudies-literature
Project description:Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.
| S-EPMC5412059 | biostudies-literature
Project description:Hydrocephalic hyh mutant mice undergo a programmed loss of the neuroepithelium/ependyma followed by a reaction of periventricular astrocytes, which form a new cell layer covering the denuded ventricular surface. We present a comparative morphological and functional study of the newly formed layer of astrocytes and the multiciliated ependyma of hyh mice. Transmission electron microscopy, immunocytochemistry for junction proteins (N-cadherin, connexin 43) and proteins involved in permeability (aquaporin 4) and endocytosis (caveolin-1, EEA1) were used. Horseradish peroxidase (HRP) and lanthanum nitrate were used to trace the intracellular and paracellular transport routes. The astrocyte layer shares several cytological features with the normal multiciliated ependyma, such as numerous microvilli projected into the ventricle, extensive cell-cell interdigitations and connexin 43-based gap junctions, suggesting that these astrocytes are coupled to play an unknown function as a cell layer. The ependyma and the astrocyte layers also share transport properties: (1) high expression of aquaporin 4, caveolin-1 and the endosome marker EEA1; (2) internalization into endocytic vesicles and early endosomes of HRP injected into the ventricle; (3) and a similar paracellular route of molecules moving between CSF, the subependymal neuropile and the pericapillary space, as shown by lanthanum nitrate and HRP. A parallel analysis performed in human hydrocephalic foetuses indicated that a similar phenomenon would occur in humans. We suggest that in foetal-onset hydrocephalus, the astrocyte assembly at the denuded ventricular walls functions as a CSF-brain barrier involved in water and solute transport, thus contributing to re-establish lost functions at the brain parenchyma-CSF interphase.
| S-EPMC3444707 | biostudies-literature