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Neurological symptoms in tuberous sclerosis complex (TSC) and associated brain lesions are thought to arise from abnormal embryonic neurogenesis due to inherited mutations in Tsc1 or Tsc2. Neurogenesis persists postnatally in the human subventricular zone (SVZ) where slow-growing tumors containing Tsc-mutant cells are generated in TSC patients. However, whether Tsc-mutant neurons from the postnatal SVZ contribute to brain lesions and abnormal circuit remodeling in forebrain structures remain unexplored. Here, we report the formation of olfactory lesions following conditional genetic Tsc1 deletion in the postnatal SVZ using transgenic mice or targeted single-cell electroporation. These lesions include migratory heterotopias and olfactory micronodules containing neurons with a hypertrophic dendritic tree. Most significantly, our data identify migrating glial and neuronal precursors that are re-routed and infiltrate forebrain structures (e.g. cortex) and become glia and neurons. These data show that Tsc1-mutant cells from the neonatal and juvenile SVZ generate brain lesions and structural abnormalities, which would not be visible using conventional non-invasive imaging. These findings also raise the hypothesis that micronodules and the persistent infiltration of cells to forebrain structures may contribute to network malfunction leading to progressive neuropsychiatric symptoms in TSC.

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IntroductionHematopoiesis is regulated by multiple mechanisms, including interaction of cell surface receptors with growth factors and cytokines. These molecules aid in the survival, proliferation, and differentiation of hematopoietic progenitors. One superfamily of receptors that binds hematopoietic growth factors is the receptor tyrosine kinase (RTK) superfamily (reviewed in 1 ). The cytokine receptor superfamily also plays an important role in this process (reviewed in 2 ).c-Kit is an RTK encoded by the c-kit proto-oncogene (reviewed in [3][4][5] ). The c-Kit ligand is stem cell factor (SCF). The absence of either SCF or c-Kit is lethal, and decreases in expression or function of ligand or receptor results in macrocytic anemia, mast cell deficiency, aberrations in pigmentation, and sterility (reviewed in 3,6,7 ). Inappropriate expression or constitutive activation of c-Kit has also been associated with human diseases, including mastocytosis, myeloid leukemia, small-cell lung carcinoma, and gastrointestinal stromal cell tumors. [8][9][10][11][12] The critical role of c-Kit in normal physiology and the association of activated mutants with human disease highlights the importance of understanding its mechanism of action. Recent work has demonstrated that SCF activates the Ras-Raf-Map kinase cascade, phosphatidylinositol 3 kinase (PI3K), and, in some lineages, the Jak/Stat pathway (reviewed in 13 ). SCF induces the association of Src, Lyn, and Fyn with c-Kit and the activation of multiple Src family members. [14][15][16][17][18][19][20] Reduction in the expression of Lyn using antisense oligonucleotides inhibits SCF-induced proliferation. 15 In addition, treatment of cells with PP1, a Src family inhibitor, does not alter the in vitro kinase activity of c-Kit but impairs SCF-induced cell-cycle progression and growth. 15,20,21 These data suggest that Lyn has an important function in SCF-induced proliferation in hematopoietic cells. However, several lines of evidence conflict with this hypothesis. First, findings using leukemic cell lines treated with pharmacologic inhibitors and antisense oligonucleotides may not be representative of normal physiology. Second, studies with c-Kit mutants incapable of directly associating with Src family members suggest this kinase family does not play a significant role in SCFmediated responses. 17,19 However, indirect activation of Src family members could be induced through other regions of c-Kit. Third, the phenotype of Lyn-deficient mice is not consistent with the abrogation of SCF-mediated responses, though compensatory mechanisms in vivo could mask highly specific defects in SCF responsiveness. [22][23][24] To understand the role of Lyn in c-Kit stimulus-response coupling mechanisms in primary hematopoietic cells, we examined SCF-mediated responses of Lyn-deficient mast cells and lineage negative (Lin Ϫ ) progenitor cells. These cells represent differentiated and undifferentiated lineages of hematopoietic cells that are both important target populations for SCF. This is of par...