loxP mediated inactivation of Pten in neural precursors during midgestation showed severe dysplasia with disturbance of the laminar organisation of the brain

The tumour suppressor gene PTEN encodes a lipid phosphatase, which has been shown to play a crucial role in the regulation of adhesion, migration, growth and apoptosis. PTEN germline mutations have been detected in several familial tumour syndromes, the most prominent of which are Cowden disease (CD) and Bannayan-Zonana (BZ) syndrome. These syndromes are characterised by developmental defects, benign tumours/hamartomas and a propensity to develop thyroid and breast cancer (Lloyd and Dennis, 1963). A subset of individuals with CD develops cerebellar gangliocytoma with abnormal and enlarged foliation caused by thickened and broadened layers of dysplastic and disorganised neuronal cells, also known as Lhermitte-Duclos disease (Lhermitte and Duclos, 1920). In addition to the disorganised cerebellar architecture, these individuals can show macrocephalia and mental retardation, and can develop seizures (Padberg et al., 1991). However, although PTEN germline mutations have been demonstrated to be associated with CD and BZ syndromes, there is a considerable variability in genotype-phenotype correlation in individuals with identified mutations, and large studies have failed to detect PTEN germ line mutations in all individuals with CD and BZ syndrome (Marsh et al., 1998a; Marsh et al., 1998b). The phenotypic variability of specific mutations suggests the involvement of further tumour modifier genes (Marsh et al., 1999). Several studies have been undertaken to elucidate the role of PTEN during development and tumourigenesis of the central nervous system. First evidence for the importance of PTEN in developmental processes was provided by the analysis of Pten–/– mice, which showed overgrowth of cells and disorganised cell layers in cephalic and caudal regions, resulting in early embryonic lethality (Di Cristofano et al., 1998; Podsypanina et al., 1999). Pten–/– embryonic stem cells fail to form embryoid bodies in vitro and to differentiate when transplanted into recipient mice suggesting a crucial role of PTEN in the differentiation process (Di Cristofano et al., 1998; Podsypanina et al., 1999) and Pten–/– embryos show an extensive proliferation and overgrowth (Stambolic et al., 1998). Recently, cre loxP mediated inactivation of Pten in neural precursors during midgestation showed severe dysplasia with disturbance of the laminar organisation of the brain 3513 Development 129, 3513-3522 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV4628