Mutations in 
            SOX2
             cause anophthalmia–esophageal–genital (AEG) syndrome

Williamson, Kathleen A.; Hever, Ann; Rainger, Joe; Rogers, R. Curtis; Magee, Alex; Fiedler, Z; Keng, Wee Teik; Sharkey, Freddie H.; McGill, Niolette I.; Hill, Clare J.; Schneider, Adele; Messina, Mario; Turnpenny, Peter D.; Fantes, Judy; Heyningen, Veronica van; FitzPatrick, David R.

doi:10.1093/hmg/ddl127

Cited by 58 publications

(79 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This hypothesis is consistent with the evidence that LIN28 negatively regulates gliogenesis independently of let-7 miRs (44), as well as our previous observation that gliogenesis is not affected by the loss of SOX2 from neural precursors (11). In humans, SOX2 haploinsufficiency results in abnormal development of the hippocampus, and epilepsy (50); anophthalmia (51); retarded growth and sensorineural deafness (52); and genital anomalies (53). Our findings suggest that some of these phenotypes could be mediated through the LIN28/let-7 pathway, thus identifying potential new targets for therapeutic intervention.…”

Section: Discussionsupporting

confidence: 90%

SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

Cimadamore

Amador-Arjona

Chen

et al. 2013

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

202

182

View full text Add to dashboard Cite

The transcription factor SRY (sex-determining region)-box 2 (SOX2) is an important functional marker of neural precursor cells (NPCs) and plays a critical role in self-renewal and neuronal differentiation; however, the molecular mechanisms underlying its functions are poorly understood. Using human embryonic stem cellderived NPCs to model neurogenesis, we found that SOX2 is required to maintain optimal levels of LIN28, a well-characterized suppressor of let-7 microRNA biogenesis. Exogenous LIN28 expression rescued the NPC proliferation deficit, as well as the early but not the late stages of the neurogenic deficit associated with the loss of SOX2. We found that SOX2 binds to a proximal site in the LIN28 promoter region and regulates LIN28 promoter acetylation, likely through interactions with the histone acetyltransferase complex. Misexpression of let-7 microRNAs in NPCs reduced proliferation and inhibited neuronal differentiation, phenocopying the loss of SOX2. In particular, we identified let-7i as a novel and potent inhibitor of neuronal differentiation that targets MASH1 and NGN1, two well-characterized proneural genes. In conclusion, we discovered the SOX2-LIN28/let-7 pathway as a unique molecular mechanism governing NPC proliferation and neurogenic potential.neural stem cells | mechanisms of pluripotency S elf-renewing, multipotent neural precursor cells (NPCs) are capable of terminally differentiating into neuronal and glial lineages during development and in the adult nervous system (1, 2). Disruption of the pathways controlling NPC biology has been implicated in various pathologies, including autism (3), Treacher Collins syndrome (4), and neural tube defects (5), emphasizing the importance of gaining a better understanding of the underlying molecular events and how they may be manipulated to treat and prevent such pathologies. The HMG-box transcription factor SOX2 is ubiquitously expressed in NPCs and supports their self-renewal (6). SOX2 is also required for neurogenesis in the central nervous system (7-10). Recently, we used human embryonic stem cells (hESCs) and mouse models to demonstrate a critical requirement for SOX2 for sensory neurogenesis in dorsal root ganglia (11). However, the mechanisms by which SOX2 functions in self-renewal and neuronal differentiation remain poorly understood.Small, noncoding microRNAs (miRNAs) are transcribed as long precursors (pri-miRNAs) that are sequentially processed by the RNases Drosha/Pasha to form pri-miRNAs and by Dicer to form the mature miRNAs of ∼20-25 nucleotides. The miRNAs function through imperfect base-pairing with hundreds of target mRNAs to trigger their degradation (or block their translation) by the RNA-induced silencing complex, RISC (12). In some cases, miRNA maturation is tightly controlled; for example, the RNA-binding protein LIN28 regulates the biogenesis of the let-7 miRNA family by inhibiting their maturation at both the primiRNA (13, 14) and premiRNA (15, 16) processing steps. Intriguingly, LIN28 protein was found to be associated with SO...

show abstract

Section: Discussionsupporting

confidence: 90%

SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

Cimadamore

Amador-Arjona

Chen

et al. 2013

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

202

182

View full text Add to dashboard Cite

show abstract

“…In severe ocular malformations, the majority of the mutations identified in the Sox2 locus are frameshift or nonsense mutations and are expected to produce a truncated Sox2 protein (7). However, missense mutations that lead to amino acid changes have been found in three cases (8,28,29). Intriguingly, two of these three missense mutations are predicted to alter the conserved residues in helices 2 and 3 of the Sox2 HMG domain (R74P and L97P, respectively), which in the pulldown assays of the present work were revealed to have a role in the interaction with the Otx2 protein ( Fig.…”

Section: Missense Mutations Identified In the Sox2 Hmg Domain Affect mentioning

confidence: 54%

Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression

Danno

Michiue

Hitachi

et al. 2008

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

101

112

View full text Add to dashboard Cite

The neural-related genes Sox2, Pax6, Otx2, and Rax have been associated with severe ocular malformations such as anophthalmia and microphthalmia, but it remains unclear as to how these genes are linked functionally. We analyzed the upstream signaling of Xenopus Rax (also known as Rx1) and identified the Otx2 and Sox2 proteins as direct upstream regulators of Rax. We revealed that endogenous Otx2 and Sox2 proteins bound to the conserved noncoding sequence (CNS1) located Ϸ2 kb upstream of the Rax promoter. This sequence is conserved among vertebrates and is required for potent transcriptional activity. Reporter assays showed that Otx2 and Sox2 synergistically activated transcription via CNS1. Furthermore, the Otx2 and Sox2 proteins physically interacted with each other, and this interaction was affected by the Sox2-missense mutations identified in these ocular disorders. These results demonstrate that the direct interaction and interdependence between the Otx2 and Sox2 proteins coordinate Rax expression in eye development, providing molecular linkages among the genes responsible for ocular malformation.anophthalmia ͉ comparative genomics ͉ microphthalmia ͉ rx1 ͉ Xenopus

show abstract

“…8 One frameshift mutation causing continued translation beyond the normal stop codon, and three missense mutations in the HMG domain have also been reported and all are associated with anophthalmia or severe microphthalmia. 9,11,13 In this family, one patient has bilateral typical optic fissure closure defects (Figure 1, III.1) and two patients have iris anomalies indicating a minor form of optic fissure closure abnormality (Figure 1, II.1 and II.9). Typical optic fissure closure defects are not usually associated with SOX2 mutations.…”

Section: Discussionmentioning

confidence: 91%

Novel SOX2 partner-factor domain mutation in a four-generation family

et al. 2009

View full text Add to dashboard Cite

Anophthalmia (no eye), microphthalmia (small eye) and associated ocular developmental anomalies cause significant visual handicap. In most cases the underlying genetic cause is unknown, but mutations in some genes, such as SOX2, cause ocular developmental defects, particularly anophthalmia, in a subset of patients. Here, we describe a four-generation family with a p.Asp123Gly mutation in the highly conserved partner-factor interaction region of the SOX2 protein, which is important for cell-specific actions of SOX2. The proband in this family has bilateral anophthalmia and several other family members have milder ocular phenotypes, including typical optic fissure coloboma. Expression studies indicate that Sox2 is expressed in the eye at the site of closure of the optic fissure during development. The SOX2 mutation in this family implicates the partner-factor interaction region of SOX2 in contributing to the specificity of SOX2 action in optic fissure closure. Our findings indicate that investigation of SOX2 in a broad range of eye anomaly patients aids in the determination of particular functions of SOX2 in development.

show abstract

Mutations in SOX2 cause anophthalmia–esophageal–genital (AEG) syndrome

Cited by 58 publications

References 0 publications

SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression

Novel SOX2 partner-factor domain mutation in a four-generation family

Contact Info

Product

Resources

About