SNX27 Deletion Causes Hydrocephalus by Impairing Ependymal Cell Differentiation and Ciliogenesis

Abstract

Hydrocephalus is a brain disorder derived from CSF accumulation due to defects in CSF clearance. Although dysfunctional apical cilia in the ependymal cell layer are causal to the onset of hydrocephalus, mechanisms underlying proper ependymal cell differentiation are largely unclear. SNX27 is a trafficking component required for normal brain function and was shown previously to suppress ␥-secretase-dependent amyloid precursor protein and Notch cleavage. However, it was unclear how SNX27-dependent ␥-secretase inhibition could contribute to brain development and pathophysiology. Here, we describe and characterize an Snx27-deleted mouse model for the ependymal layer defects of deciliation and hydrocephalus. SNX27 deficiency results in reductions in ependymal cells and cilia density, as well as severe postnatal hydrocephalus. Inhibition of Notch intracellular domain signaling with ␥-secretase inhibitors reversed ependymal cells/cilia loss and dilation of lateral ventricles in Snx27-deficient mice, giving strong indication that Snx27 deletion triggers defects in ependymal layer formation and ciliogenesis through Notch hyperactivation. Together, these results suggest that SNX27 is essential for ependymal cell differentiation and ciliogenesis, and its deletion can promote hydrocephalus pathogenesis.

MT1-MMP deficiency leads to defective ependymal cell maturation, impaired ciliogenesis, and hydrocephalus

“…In mice, the most prominent phenotypes are dome-shaped skull and enlarged ventricles caused by the accumulation of CSF, due to either the obstruction of the ventricular system or defects in the ECs. For example, mutations in genes encoding for structural and functional proteins of cilia, including TMEM67, MKS1, SNX27, and CC2D2A, result in congenital hydrocephalus (5,55,56).…”

“…ECs are derived from radial glia cells at birth. Defects in either differentiation or maturation of ECs can give rise to hydrocephalus (4,5,(44)(45)(46). To investigate the potential defects in the differentiation and maturation of ECs, we first examined the density of RGCs at the apical surface of LVs at P0 by immunofluorescence staining using antibodies against the RGC marker, BLBP.…”

“…The identification of genetic risk factors is fundamental to our understanding of the molecular mechanisms underlying the pathogenesis of hydrocephalus and serves as the key in the diagnosis and management (3,4). Recent studies using genetically modified mouse models revealed that Snx27, Ccdc39, and Ulk4 are disease genes for congenital hydrocephalus (5)(6)(7).…”

Sorting nexin 27 (SNX27) variants associated with seizures, developmental delay, behavioral disturbance, and subcortical brain abnormalities

“…SNX27 deficient ( Snx27 −/− ) mice exhibit reduced embryonic survival, marked postnatal growth restriction and lethality prior to weaning . Snx27 −/− mice were also shown to develop progressive hydrocephalous . In comparison, Snx27 +/− mice have normal neuroanatomy, but exhibit deficits in learning and memory, with associated impairment in synaptic transmission and plasticity …”

“…14,18 Snx27 −/− mice were also shown to develop progressive hydrocephalous. 19 In comparison, Snx27 +/− mice have normal neuroanatomy, but exhibit deficits in learning and memory, with associated impairment in synaptic transmission and plasticity. 18 In 2015, four siblings within a consanguineous Palestinian family were found to have a homozygous frameshift variant, c.515_516del;p.…”