Disruption of Wave-associated Rac GTPase-activating Protein (Wrp) Leads to Abnormal Adult Neural Progenitor Migration Associated with Hydrocephalus

Benjamin R Carlson,Hyun Kim,Il Hwan Kim,Scott H Soderling,Clifford C Heindel

doi:10.1074/jbc.m112.398834

Benjamin R Carlson, Hyun Kim + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m112.398834

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Abstract

Hydrocephalus is the most common developmental disability and leading cause of brain surgery for children. Current treatments are limited to surgical intervention, as the factors that contribute to the initiation of hydrocephalus are poorly understood. Here, we describe the development of obstructive hydrocephalus in mice that are null for Wrp (Srgap3). Wrp is highly expressed in the ventricular stem cell niche, and it is a gene required for cytoskeletal organization and is associated with syndromic and psychiatric disorders in humans. During the postnatal period of progenitor cell expansion and ventricular wall remodeling, loss of Wrp results in the abnormal migration of lineage-tagged cells from the ventricular region into the corpus callosum. Within this region, mutant progenitors appear to give rise to abnormal astroglial cells and induce periventricular lesions and hemorrhage that leads to cerebral aqueductal occlusion. These results indicate that periventricular abnormalities arising from abnormal migration from the ventricular niche can be an initiating cause of noncommunicating hydrocephalus.

Highlights

Obstructive hydrocephalus results from blockage of the cerebral aqueduct, a poorly understood process
The LV size of Wrp KO mice was normal until postnatal day 9 (P9), and by P12 the KO brains (n ϭ 3 for WT; n ϭ 4 for KO) began to display enlarged LVs (t ϭ 4.29, df ϭ 5, p Ͻ 0.01) that were more severe at P40 (n ϭ 3 for WT; n ϭ 4 for KO) (t ϭ 14.87, df ϭ 5, p Ͻ 0.0001) (Fig. 1E)
These data indicate that the hydrocephalus in the Wrp KO mice initiates at an early postnatal stage and results in obstructive hydrocephalus

Summary

Background

Obstructive hydrocephalus results from blockage of the cerebral aqueduct, a poorly understood process. During the postnatal period of progenitor cell expansion and ventricular wall remodeling, loss of Wrp results in the abnormal migration of lineage-tagged cells from the ventricular region into the corpus callosum Within this region, mutant progenitors appear to give rise to abnormal astroglial cells and induce periventricular lesions and hemorrhage that leads to cerebral aqueductal occlusion. Mutant progenitors appear to give rise to abnormal astroglial cells and induce periventricular lesions and hemorrhage that leads to cerebral aqueductal occlusion These results indicate that periventricular abnormalities arising from abnormal migration from the ventricular niche can be an initiating cause of noncommunicating hydrocephalus. The debris appears to be released into the ventricular space, resulting in blockage of the aqueduct and leading to obstructive hydrocephalus Together, these findings suggest that abnormalities in the neural stem cell niche can be an initiating factor for the pathophysiology of hydrocephalus

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION