Loss of adenomatous polyposis coli in Bergmann glia disrupts their unique architecture and leads to cell nonautonomous neurodegeneration of cerebellar Purkinje neurons

Abstract

The tumor suppressor adenomatous Polyposis Coli (APC) is a multifunctional protein that inhibits the Wnt/beta-catenin signaling pathway and regulates the microtubule and actin cytoskeletons. Using conditional knockout (CKO) mice in which the APC gene is inactivated in glial fibrillary acidic protein (GFAP)-expressing cells, we show a selective and critical role for APC in maintaining the morphology and function of cerebellar Bergmann glia. APC-CKO mice developed Bergmann glia normally until the accumulation of beta-catenin started around postnatal day 10 (P10). Their radial fibers then became shortened with a marked reduction of branching collaterals and their cell bodies translocated into the molecular layer followed by loss of their pial contact and transformation into stellate-shaped cells by P21. Purkinje neurons were normal in appearance and number at P21, but there was significant loss of Purkinje neurons and cerebellar atrophy by middle age. Outside the cerebellum, neither beta-catenin accumulation nor morphological changes were identified in GFAP-expressing astroglia, indicating region-specific effects of APC deletion and an essential role for APC in maintaining the unique morphology of Bergmann glia as compared with other astroglia. These results demonstrate that loss of APC selectively disrupts the Bergmann glial scaffold in late postnatal development and leads to cerebellar degeneration with loss of Purkinje neurons in adults, providing another potential mechanism for region-specific non-cell autonomous neurodegeneration.

Hypothalamic radial glia function as self-renewing neural progenitors in the absence of Wnt/ß-catenin signaling

“…Consistent with studies of non-neural stem cells (Lowry et al, 2005;Blanpain and Fuchs, 2009;Farin et al, 2012), our data show that Wnt/β-catenin signaling is only necessary for the terminal differentiation of specific neuronal progeny. Furthermore, and as shown for radial glia in other brain regions (Wang et al, 2011), we find that ectopic Wnt/β-catenin activity inhibits the expansion of neurogenic radial glia in the hypothalamus. Together, these data suggest that the most generally conserved role for Wnt pathway activity in neural progenitors is in promoting neurogenesis, and that other functions may differ between diverse stem and progenitor cell populations.…”

“…Previous work from our laboratory showed that Wnt/β-catenin signaling is required for postembryonic hypothalamic neurogenesis , and other studies have also led to the hypothesis that pathway activity promotes radial glial differentiation (Lee et al, 2006;Wang et al, 2011Wang et al, , 2012Choe and Pleasure, 2012;Varela-Nallar and Inestrosa, 2013). By contrast, Wnt/β-catenin signaling has also been shown to promote the self-renewal and expansion of neural stem cells in the mammalian telencephalic subventricular zone and dentate gyrus (Qu et al, 2010).…”

Adenomatous polyposis coli regulates radial axonal sorting and myelination in the PNS

“…S5). Prior reports indicated that the interaction of APC with the cytoskeleton may regulate cell process formation and extension in radial glia, astrocytes and neurons (Imura et al, 2010;Wang et al, 2011;Yokota et al, 2009). In order to test the possibility that APC also controls process extension in Schwann cells, we traced and measured the length of these cells in 3DEM serial sciatic nerve sections of Apc lox/lox ;P0-Cre and Apc lox/lox control mice.…”

Adenomatous Polyposis Coli Regulates Oligodendroglial Development

“…Prior reports indicated that APC in the CNS regulates process formation and extension by radial glia, astroglia, and neurons, proliferation of neuroblasts, and trophic interactions between Bergmann glia and Purkinje cells (Yokota et al, 2009; Imura et al, 2010; Wang et al, 2011). A recent study (Fancy et al, 2009) demonstrated that oligodendroglial differentiation and remyelination are delayed in adult Apc min/+ mice ( Apc multiple intestinal neoplasia, one-allele truncated mutation of Apc , lacking β-catenin binding domain ) (Moser et al, 1993) following lysolecithin-induced demyelination, and suggested, but did not prove, that this delay was attributable to dysregulation of Wnt/β-catenin signaling in these Apc -haploinsufficient mice.…”

“…Does single-allele APC truncation lead to upregulation of Wnt/β-catenin signaling in the CNS? Since axonal activity regulates OPC differentiation (Barres and Raff, 1999), were the delays in oligodendrogenesis and remyelination secondary to axonal dysfunction elicited by the Apc mutation (Zhou et al, 2004; Chen et al, 2011; Wang et al, 2011), or does APC exert cell-autonomous effects on oligodendroglial differentiation?…”