S6k1 is not required for Pten-deficient neuronal hypertrophy.
The tumor suppressor PTEN (phosphatase and tensin homolog) plays a critical role in the development and maintenance of the mammalian nervous system. Effects of inherited mutation of PTEN are highly variable and include macrocephaly, Lhermitte-Duclos disease (LDD) caused by a hamartomatous enlargement of the cerebellum, ataxia, seizures and autism, in addition to cancer predisposition. In the mouse, selective inactivation of Pten in post-mitotic granule neurons of the cerebellum and dentate gyrus showed that Pten was required for proper regulation of neuronal nuclear and soma size. Hypertrophy of Pten-deficient neurons required the activity of the serine-threonine kinase mTor. mTor is a master regulator of cell and organ growth which can trigger a cascade of downstream signaling pathways involving, in part, components of the translational machinery, including S6k1 and its substrate the ribosomal protein S6. Deletion of S6k1 in mice results in decreased size. Therefore, to determine the relative contribution of S6k1 to Pten-deficient neuronal hypertrophy in vivo, we crossed Pten brain-conditional knockouts with S6k1 null mice. Double mutant mice show no reversion or improvement in their Pten-related size and neurological defects including enlarged cerebella and dentate gyri with increased size of neuronal nuclei and somata, ataxia, and premature death. The hypertrophic Pten/S6k1-deficient neurons contained high levels of phosphorylated S6, similar to Pten-deficient neurons, suggesting that the mTor/S6k/S6 branch of the pathway was still active. Thus, we conclude that S6k1 is not required to cause hypertrophy of Pten-deficient neurons. This study reveals a cell type-dependent role for S6k1 in PI3K-dependent hypertrophy.
Chalhoub
Nader
N
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Kozma
Sara C
SC
Baker
Suzanne J
SJ
D000818:Animals; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000033:anatomy & histology / Q000166:cytology; D002452:Cell Count; D002467:Cell Nucleus / Q000648:ultrastructure; D048429:Cell Size; D002531:Cerebellum / Q000166:cytology / Q000648:ultrastructure; D018891:Dentate Gyrus / Q000166:cytology / Q000648:ultrastructure; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D009929:Organ Size / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
D011494:Protein Kinases; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; D051059:PTEN Phosphohydrolase