Combinatorial regulation of optic cup progenitor cell fate by SOX2 and PAX6

Matsushima, Danielle; Heavner, Whitney E.; Pevny, Larysa

doi:10.1242/dev.055178

Cited by 100 publications

(124 citation statements)

References 83 publications

(93 reference statements)

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“…Here, we show a complementary expression pattern of Sox2 and Pax6 at E13.5 and E16.5, suggesting that the Sox2/Pax6 ratio is involved in the regulation of cell specification of fate-restricted PCs in the developing cerebellum. An analogous mechanism has been described for proper regionalization of the optic cup during eye development [33]. On the other hand, p21 has been recently shown as a major player in the control of expansion of NSCs through negative regulation of the Sox2 gene [34].…”

Section: Discussionmentioning

confidence: 59%

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

et al. 2013

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Neural stem cells are highly susceptible to radiogenic DNA damage, however, little is known about their mechanisms of DNA damage response (DDR) and the long-term consequences of genotoxic exposure. Patched1 heterozygous mice (Ptc1 1/2 ) provide a powerful model of medulloblastoma (MB), a frequent pediatric tumor of the cerebellum. Irradiation of newborn Ptc1 1/2 mice dramatically increases the frequency and shortens the latency of MB. In this model, we investigated the mechanisms through which multipotent neural progenitors (NSCs) and faterestricted progenitor cells (PCs) of the cerebellum respond to DNA damage induced by radiation, and the long-term developmental and oncogenic consequences. These responses were assessed in mice exposed to low (0.25 Gy) or high (3 Gy) radiation doses at embryonic day 13.5 (E13.5), when NSCs giving rise to the cerebellum are specified but the external granule layer (EGL) has not yet formed, or at E16.5, during the expansion of granule PCs to form the EGL. We found crucial differences in DDR and apoptosis between NSCs and fate-restricted PCs, including lack of p21 expression in NSCs. NSCs also appear to be resistant to oncogenesis from low-dose radiation exposure but more vulnerable at higher doses. In addition, the pathway to DNA repair and the pattern of oncogenic alterations were strongly dependent on age at exposure, highlighting a differentiation-stage specificity of DNA repair pathways in NSCs and PCs. These findings shed light on the mechanisms used by NSCs and PCs to maintain genome integrity during neurogenesis and may have important implications for radiation risk assessment and for development of targeted therapies against brain tumors.

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Section: Discussionmentioning

confidence: 59%

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

et al. 2013

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“…Therefore, Sox2 also plays an essential context-dependent role in the CNS. Sox2 forms a complex with its partners to function, and Pax6 is one of the factors that interact with Sox2 in both stem/progenitor cells (eg, NSCs in the CNS and optic cup progenitor cells) and terminally differentiated cells (eg, lens cells) [16,[47][48][49]. In the OE, Pax6 and Sox2 are coexpressed in HBCs, GBCs, and SUSs, and they are believed to suppress neuronal differentiation [6].…”

Section: Discussionmentioning

confidence: 99%

Horizontal Basal Cell-Specific Deletion ofPax6Impedes Recovery of the Olfactory Neuroepithelium Following Severe Injury

Suzuki

Sakurai

Yamazaki

et al. 2015

Stem Cells and Development

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In the mammalian olfactory epithelium (OE), olfactory receptor neurons (ORNs) are continuously regenerated throughout the animal's lifetime. Horizontal basal cells (HBCs) in the OE express the epithelial marker keratin 5 (K5) and the stem cell marker Pax6 and are considered relatively quiescent tissue stem cells in the OE. Pax6 is a key regulator of several developmental processes in the central nervous system and in sensory organs. Although Pax6 is expressed in the OE, its precise role remains unknown, particularly with respect to stem celllike HBCs. To investigate the function of Pax6 in the developmental and regenerative processes in the OE, we generated conditional Pax6-knockout mice carrying a loxP-floxed Pax6 gene. Homozygous Pax6-floxed mice were crossed with K5-Cre transgenic mice to generate HBC-specific Pax6-knockout (Pax6-cKO) mice. We confirmed that the deletion of Pax6 expression in HBCs was sufficiently achieved in zone 1 of the OE in Pax6-cKO mice 3 days after methimazole-induced severe damage. In this condition, regeneration of the OE was dramatically impaired; both OE thickness and the number of ORNs were significantly decreased in the regenerated OE of Pax6-cKO mice. These results suggest that Pax6 expression is essential for HBCs to differentiate into neuronal cells during the regeneration process following severe injury.

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“…The specific expression of different Sox2 interacting/ cooperating factors in various tissues might impart regional specificity to the defects caused by the absence of Sox2; indeed, an important (antagonistic) relationship of Sox2 with Pax6 was reported in a study of the development of neural competence in the optic cup (Matsushima et al, 2011).…”

Section: Research Articlementioning

confidence: 99%

Sox2 is required for embryonic development of the ventral telencephalon through the activation of the ventral determinants Nkx2.1 and Shh

et al. 2013

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SUMMARYThe Sox2 transcription factor is active in stem/progenitor cells throughout the developing vertebrate central nervous system. However, its conditional deletion at E12.5 in mouse causes few brain developmental problems, with the exception of the postnatal loss of the hippocampal radial glia stem cells and the dentate gyrus. We deleted Sox2 at E9.5 in the telencephalon, using a Bf1-Cre transgene. We observed embryonic brain defects that were particularly severe in the ventral, as opposed to the dorsal, telencephalon. Important tissue loss, including the medial ganglionic eminence (MGE), was detected at E12.5, causing the subsequent impairment of MGEderived neurons. The defect was preceded by loss of expression of the essential ventral determinants Nkx2.1 and Shh, and accompanied by ventral spread of dorsal markers. This phenotype is reminiscent of that of mice mutant for the transcription factor Nkx2.1 or for the Shh receptor Smo. Nkx2.1 is known to mediate the initial activation of ventral telencephalic Shh expression. A partial rescue of the normal phenotype at E14.5 was obtained by administration of a Shh agonist. Experiments in Medaka fish indicate that expression of Nkx2.1 is regulated by Sox2 in this species also. We propose that Sox2 contributes to Nkx2.1 expression in early mouse development, thus participating in the region-specific activation of Shh, thereby mediating ventral telencephalic patterning induction.

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Combinatorial regulation of optic cup progenitor cell fate by SOX2 and PAX6

Cited by 100 publications

References 83 publications

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

Horizontal Basal Cell-Specific Deletion ofPax6Impedes Recovery of the Olfactory Neuroepithelium Following Severe Injury

Sox2 is required for embryonic development of the ventral telencephalon through the activation of the ventral determinants Nkx2.1 and Shh

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