A conditional mouse model for the characterization of mTORC1 function in muscle and brain

The Ser/Thr kinase mammalian target of rapamycin (mTOR) regulates cell growth in
response to extracellular stimulation with growth factors and to intracellular factors
that sense the nutritional and the energy state of the cell. mTOR forms two distinct
multiprotein complexes, the rapamycin-sensitive mTOR complex 1 (mTORC1) and
mTORC2. Most characterized functions of mTOR are mediated by mTORC1.
However, direct investigation of the in vivo function in most tissues including brain
and muscle has been occluded by the early embryonic lethality of deficient mice for
all mTORC1 members. Here, I describe the generation and characterization of mice
that are deficient for raptor, an essential component of mTORC1, in skeletal muscle
fibers and the developing brain.
Analysis of the raptor-deficient brain reveals a general growth defect that evenly
affects the whole organ. A decrease in cell size and cell number underlies the
observed microcephaly. This is in accordance to earlier studies which assign to
mTORC1 a role as controller of cell size and cell cycle. Beside this, mTORC1
controls several more specific aspects of brain development. Glial differentiation is
disturbed and this is paralleled by a decrease of Stat3 activity, a member of the
Jak/Stat pathway that was previously involved in gliogenesis. Loss of the glial
network in the dentate gyrus likely causes malformations of the developing granule
cell layer. Furthermore, I describe an unexpected role of mTORC1 in the formation of
hippocampal and cortical layers.
Muscle-specific knockout (ko) mice develop a progressive muscle dystrophy and
show changes in muscle metabolism. Based on alterations in the activation state and
expression levels, we provide evidence that this phenotype is accounted for by
PGC1alpha as well as Akt/PKB.
In summary, this work provides evidence, that raptor is important for postnatal
survival both, in muscle and the brain. Beside the generalized changes in cell growth,
both ko models provide first evidence in vivo that mTORC1 regulates specific
aspects of metabolism and that it differentially affects both glial and neuronal
differentiation by affecting cell-specific pathways.