WNT5a Regulates Epithelial Morphogenesis in the Developing Choroid Plexus

Abstract

The choroid plexus (CP) is the predominant supplier of cerebral spinal fluid (CSF) and the site of the blood–CSF barrier and is thus essential for brain development and central nervous system homeostasis. Despite these crucial roles, our understanding of the molecular and cellular processes giving rise to the CPs within the ventricles of the mammalian brain is very rudimentary. Here, we identify WNT5a as an important regulator of CP development, where it acts as a pivotal factor driving CP epithelial morphogenesis in all ventricles. We show that WNT5a is essential for the establishment of a cohesive epithelium in the developing CP. We find that in its absence all CPs are substantially reduced in size and complexity and fail to expand into the ventricles. Severe defects were observed in the epithelial cytoarchitecture of all Wnt5a−/− CPs, exemplified by loss of apicobasally polarized morphology and detachment from the ventricular surface and/or basement membrane. We also present evidence that the WNT5a receptor, RYK, and the RHOA kinase, ROCK, are required for normal CP epithelial morphogenesis. Our study, therefore, reveals important insights into the molecular and cellular mechanisms governing CP development.

Emergence and Developmental Roles of the Cerebrospinal Fluid System

“…Developmentally, the ChP emerges from the dorsal midline and rhombic lip lineages (Currle et al, 2005;Hunter and Dymecki, 2007;Langford et al, 2020;Liddelow et al, 2010;Monuki et al, 2001;Shannon et al, 2018;Wilting and Christ, 1989). There is one ChP in each ventricle.…”

“…Genetic factors controlling ChP progenitor cell proliferation and differentiation are still under investigation. Loss of Lhx2 in the roof plate induces massive overspecification of ChP epithelium (Monuki et al, 2001), and loss of Wnt5a results in reduction of all ChP tissues and a failure to expand into the ventricles (Langford et al, 2020).…”

Adrenergic activation modulates the signal from the Reissner fiber to cerebrospinal fluid-contacting neurons during development

“…It has recently emerged that the cerebrospinal fluid (CSF) contains many signals important for cell differentiation, and is an important route for the control of morphogenesis ( Fame and Lehtinen, 2020 ). The CSF is a complex liquid filling the central nervous system cavities containing a set of diffusible signaling cues guiding neurogenesis ( Lehtinen et al, 2011 ) and brain morphology in a tissue autonomous manner ( Kaiser et al, 2019 ; Langford et al, 2020 ). The CSF circulation is in part generated by the coordinated movement of cilia projecting to the lumen of brain ventricles and central canal of the spinal cord ( Faubel et al, 2016 ; Hagenlocher et al, 2013 ; Olstad et al, 2019 ; Sternberg et al, 2018 ; Thouvenin et al, 2020 ).…”

The adenosine A2Areceptor alleviates postoperative delirium‐like behaviors by restoring blood cerebrospinal barrier permeability in rats

“…RhoA, a major GTPase of the Rho family, is a small guanosine triphosphate‐binding protein, and its well‐known downstream effector Rho‐associated protein kinase (ROCK) regulates cellular contraction, actin cytoskeleton organization, cell adhesion, morphology, gene expression, and motility (Amano et al., 2010; Gong et al., 2020). Accumulating evidence has suggested that the RhoA/ROCK pathway participates in regulating the structure and function of barriers (Langford et al., 2020; Xue et al., 2019), including the BBB and BCB. ROCK contains two isoforms, ROCK1 and ROCK2.…”