Constitutive activation of β-catenin in neural progenitors results in disrupted proliferation and migration of neurons within the central nervous system

TY - JOUR

T1 - Constitutive activation of β-catenin in neural progenitors results in disrupted proliferation and migration of neurons within the central nervous system

AU - Pöschl, Julia

AU - Grammel, Daniel

AU - Dorostkar, Mario M

AU - Kretzschmar, Hans A

AU - Schüller, Ulrich

N1 - Copyright © 2013 Elsevier Inc. All rights reserved.

PY - 2013/2/15

Y1 - 2013/2/15

N2 - Wnt signaling is known to play crucial roles in the development of multiple organs as well as in cancer. In particular, constitutive activation of Wnt/β-Catenin signaling in distinct populations of forebrain or brainstem precursor cells has previously been shown to result in dramatic brain enlargement during embryonic stages of development as well as in the formation of medulloblastoma, a malignant brain tumor in childhood. In order to extend this knowledge to postnatal stages of both cerebral and cerebellar cortex development, we conditionally activated Wnt signaling by introducing a dominant active form of β-catenin in hGFAP-positive neural precursors. Such mutant mice survived up to 21 days postnatally. While the mice revealed enlarged ventricles and an initial expansion of the Pax6-positive ventricular zone, Pax6 expression and proliferative activity in the ventricular zone was virtually lost by embryonic day 16.5. Loss of Pax6 expression was not followed by expression of the subventricular zone marker Tbr2, indicating insufficient neuronal differentiation. In support of this finding, cortical thickness was severely diminished in all analyzed stages from embryonic day 14.5 to postnatal day 12, and appropriate layering was not detectable. Similarly, cerebella of hGFAP-cre::Ctnnb1(ex3)(Fl/+) mice were hypoplastic and displayed severe lamination defects. Constitutively active β-Catenin induced inappropriate proliferation of granule neurons and inadequate development of Bergmann glia, thereby preventing regular migration of granule cells and normal cortical layering. We conclude that Wnt signaling has divergent roles in the central nervous system and that Wnt needs to be tightly controlled in a time- and cell type-specific manner.

AB - Wnt signaling is known to play crucial roles in the development of multiple organs as well as in cancer. In particular, constitutive activation of Wnt/β-Catenin signaling in distinct populations of forebrain or brainstem precursor cells has previously been shown to result in dramatic brain enlargement during embryonic stages of development as well as in the formation of medulloblastoma, a malignant brain tumor in childhood. In order to extend this knowledge to postnatal stages of both cerebral and cerebellar cortex development, we conditionally activated Wnt signaling by introducing a dominant active form of β-catenin in hGFAP-positive neural precursors. Such mutant mice survived up to 21 days postnatally. While the mice revealed enlarged ventricles and an initial expansion of the Pax6-positive ventricular zone, Pax6 expression and proliferative activity in the ventricular zone was virtually lost by embryonic day 16.5. Loss of Pax6 expression was not followed by expression of the subventricular zone marker Tbr2, indicating insufficient neuronal differentiation. In support of this finding, cortical thickness was severely diminished in all analyzed stages from embryonic day 14.5 to postnatal day 12, and appropriate layering was not detectable. Similarly, cerebella of hGFAP-cre::Ctnnb1(ex3)(Fl/+) mice were hypoplastic and displayed severe lamination defects. Constitutively active β-Catenin induced inappropriate proliferation of granule neurons and inadequate development of Bergmann glia, thereby preventing regular migration of granule cells and normal cortical layering. We conclude that Wnt signaling has divergent roles in the central nervous system and that Wnt needs to be tightly controlled in a time- and cell type-specific manner.

KW - Animals

KW - Blotting, Western

KW - Brain

KW - Cell Movement

KW - Cell Proliferation

KW - Central Nervous System

KW - Cerebellum

KW - Glial Fibrillary Acidic Protein

KW - HEK293 Cells

KW - Humans

KW - Immunohistochemistry

KW - Kaplan-Meier Estimate

KW - Mice

KW - Mice, Transgenic

KW - Microscopy, Confocal

KW - Neural Stem Cells

KW - Neurons

KW - Time Factors

KW - Tissue Culture Techniques

KW - Wnt Signaling Pathway

KW - beta Catenin

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.ydbio.2012.12.001

DO - 10.1016/j.ydbio.2012.12.001

M3 - SCORING: Journal article

C2 - 23237957

VL - 374

SP - 319

EP - 332

JO - DEV BIOL

JF - DEV BIOL

SN - 0012-1606

IS - 2

ER -