Akt-1 Expression Level Regulates CNS Precursors

Sinor, Amy D.; Lillien, Laura

doi:10.1523/jneurosci.1470-04.2004

Cited by 109 publications

(106 citation statements)

References 60 publications

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“…It is becoming recognized that the absolute level of a specific transcription factor is an important component of the mechanism of lineage specific regulation (Kulessa et al 1995;DeKoter and Singh 2000;Motohashi et al 2000Motohashi et al , 2004Emambokus et al 2003). Moreover, it has been proposed that neural progenitor cell heterogeneity is triggered in part through a gene-dosage effect (Marquardt and Gruss 2002;Sinor and Lillien 2004).…”

Section: Eye Morphogenesis In Sox2 Hypomorphic Micementioning

confidence: 99%

SOX2 is a dose-dependent regulator of retinal neural progenitor competence

Taranova¹,

Magness

Fagan³

et al. 2006

Genes Dev.

503

508

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Approximately 10% of humans with anophthalmia (absent eye) or severe microphthalmia (small eye) show haploid insufficiency due to mutations in SOX2, a SOXB1-HMG box transcription factor. However, at present, the molecular or cellular mechanisms responsible for these conditions are poorly understood. Here, we directly assessed the requirement for SOX2 during eye development by generating a gene-dosage allelic series of Sox2 mutations in the mouse. The Sox2 mutant mice display a range of eye phenotypes consistent with human syndromes and the severity of these phenotypes directly relates to the levels of SOX2 expression found in progenitor cells of the neural retina. Retinal progenitor cells with conditionally ablated Sox2 lose competence to both proliferate and terminally differentiate. In contrast, in Sox2 hypomorphic/null mice, a reduction of SOX2 expression to <40% of normal causes variable microphthalmia as a result of aberrant neural progenitor differentiation. Furthermore, we provide genetic and molecular evidence that SOX2 activity, in a concentration-dependent manner, plays a key role in the regulation of the NOTCH1 signaling pathway in retinal progenitor cells. Collectively, these results show that precise regulation of SOX2 dosage is critical for temporal and spatial regulation of retinal progenitor cell differentiation and provide a cellular and molecular model for understanding how hypomorphic levels of SOX2 cause retinal defects in humans.[Keywords: SOX2; allelic series; retinal progenitor identity; dosage regulation; anopthalmia, microapthalmia] Supplemental material is available at www.genesdev.org. It has recently been shown that mutations in SOX2 a SOXB1-HMG box transcription factor whose expression universally marks neural stem and progenitor cells throughout the CNS including the neural retina (Collignon et al. 1996;Zappone et al. 2000;D'Amour and Gage 2003;Ellis et al. 2004;Ferri et al. 2004), are associated with retinal and ocular malformations in humans. The resulting haploid insufficiency at the SOX2 locus occurs in ∼10% of human individuals with anophthalmia or severe microphthalmia (Fantes et al. 2003;Fitzpatrick and van Heyningen 2005;Hagstrom et al. 2005; Ragge et al. 2005a,b;Zenteno et al. 2005). Most mutations identified to date are point mutations leading to truncations of SOX2, while a smaller class of mutations includes microdeletions and missense point mutations. Interestingly, all mutations produce hypomorphic conditions, where residual SOX2 expression and function are still preserved, albeit at lower levels, leading to the highly variable severity of the clinical phenotype. In this regard, the SOX2 mutations in humans and the clinical consequence of reduced functional levels of SOX2 suggest a dosage-dependent role for SOX2 during retinal progenitor differentiation.To date, the importance of SOX2 in the nervous system has been highlighted by misexpression and domi-

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Section: Eye Morphogenesis In Sox2 Hypomorphic Micementioning

confidence: 99%

SOX2 is a dose-dependent regulator of retinal neural progenitor competence

Taranova¹,

Magness

Fagan³

et al. 2006

Genes Dev.

503

508

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show abstract

“…This signaling module plays a pivotal role in the regulation of cell survival, proliferation, and size in many systems (25)(26)(27)(28). In fact, a number of studies has suggested the roles of the PI3K-Akt pathway in NPC proliferation and/or differentiation (29)(30)(31)(32)(33). However, even though PDK1 and all 3 members of the Akt family are expressed in the developing CNS, genetic evidence for their importance in CNS development is lacking.…”

mentioning

confidence: 99%

Selective induction of neocortical GABAergic neurons by the PDK1-Akt pathway through activation of Mash1

Oishi

Watatani

Itoh

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Increased Akt-1 expression in cortical progenitors enhances proliferation and survival in vitro. This process depends on mTOR activity, and rapamycin has been shown to eliminate the Akt-1-mediated increase in stem cells and to reduce proliferation (Sinor and Lillien, 2004). Moreover, Notch ligand can expand stem cells both in vitro and in vivo.…”

Section: Review Of Zeng Et Almentioning

confidence: 99%