Brain Abnormalities on MR Imaging in Patients with Retinoblastoma

Rodjan, Firazia; Graaf, Pim de; Moll, Annette C.; Imhof, Saskia M.; Verbeke, Jonathan; Sánchez, Esther; Castelijns, Jonas A.

doi:10.3174/ajnr.a2102

Cited by 32 publications

(23 citation statements)

References 26 publications

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“…Moreover, KO mouse models have revealed the role of RB during neuronal differentiation and migration, as well as in the regulation of cell death in the embryo and adult brain (Andrusiak et al, 2011;Ghanem et al, 2012;McClellan et al, 2007;Christie et al, 2014;Ferguson et al, 2005;Macleod et al, 1996;Vandenbosch et al, 2016;Yu et al, 2012). The finding that lack of the RB1 gene is associated with structural brain abnormalities in human (Mitter et al, 2011;Rodjan et al, 2010), and inactivation of RB family proteins affects cell cycle and cell death in human ESCs (Conklin et al, 2012), suggest that RB might have a role during human brain development. However, the function of RB function in human development is still a mystery.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the lack of neuronal morphology in Tuj1 + cells within KO teratomas, this result supports the role of RB in proper cell migration during human brain development. This ectopic migration, in addition to the cell proliferation increase mentioned above, could explain the macrocephaly described in individuals who lack RB (Mitter et al, 2011;Rodjan et al, 2010). Clearly, more questions remain, such as whether VLDLR is strictly required for the ectopic migration observed in RB1-KO organoids.…”

Section: Effect Of Rb In Neuronal Migrationmentioning

confidence: 99%

“…In human, the lack of RB has been associated with structural brain abnormalities, such as macrocephaly and hypoplastic corpus callosum (Mitter et al, 2011;Rodjan et al, 2010), suggesting that RB may be required in human brain development. As human brains have a marked expansion of cerebral cortex with a unique outer subventricular zone compared with rodents (Hoerder-Suabedissen and Molnár, 2015;Kelava and Lancaster, 2016;Hansen et al, 2010), RB may affect human brain development in a different manner than it has been described in mice.…”

Section: Introductionmentioning

confidence: 99%

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RB controls growth, survival, and neuronal migration in human cerebral organoids

et al. 2017

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The tumor suppressor retinoblastoma protein (RB) regulates S-phase cell cycle entry via E2F transcription factors. Knockout (KO) mice have shown that RB plays roles in cell migration, differentiation and apoptosis, in developing and adult brain. In addition, the RB family is required for self-renewal and survival of human embryonic stem cells (hESCs). Since little is known about the role of RB in human brain development, we investigated its function in cerebral organoids differentiated from gene-edited hESCs lacking RB. We show that RB is abundantly expressed in neural stem and progenitor cells in organoids at 15 and 28 days of culture. RB loss promoted S-phase entry in DCX + cells and increased apoptosis in Sox2 + neural stem and progenitor cells, and in DCX + and Tuj1 + neurons. Associated with these cell cycle and pro-apoptotic effects, we observed increased CCNA2 and BAX gene expression, respectively. Moreover, we observed aberrant Tuj1 + neuronal migration in RB-KO organoids and upregulation of the gene encoding VLDLR, a receptor important in reelin signaling. Corroborating the results in RB-KO organoids in vitro, we observed ectopically localized Tuj1 + cells in RB-KO teratomas grown in vivo. Taken together, these results identify crucial functions for RB in the cerebral organoid model of human brain development.

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Rb In Neuronal Migrationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RB controls growth, survival, and neuronal migration in human cerebral organoids

et al. 2017

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“…Corpus callosum hypoplasia has also been reported in two patients with deletions 13q13.1q21.1 and 13q14.11q31.1 mapped by array CGH. 14 In the study by Rodjan et al, 37 MRI scan in seven patients with a 13q deletion showed corpus callosum agenesis in one patient and a Dandy-Walker variant in another patient, but locations of the deletions were not reported. Ballarati et al 13 and Kirchhoff et al 30 refined the region 13q32.3q33.1 as a critical region for corpus callosum agenesis but no specific candidate gene was found.…”

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confidence: 99%

Genotype–phenotype correlations in patients with retinoblastoma and interstitial 13q deletions

et al. 2011

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Patients with an interstitial 13q deletion that contains the RB1 gene show retinoblastoma and variable clinical features. Relationship between phenotypic expression and loss of specific neighboring genes are unresolved, yet. We obtained clinical, cytogenetic and molecular data in 63 patients with an interstitial 13q deletion involving RB1. Whole-genome array analysis or customized high-resolution array analysis for 13q14.11q14.3 was performed in 38 patients, and cytogenetic analysis was performed in 54 patients. Deletion sizes ranged between 4.2 kb and more than 33.43 Mb; breakpoints were non-recurrent. Sequence analysis of deletion junctions in five patients revealed microhomology and insertion of 2-34 base pairs suggestive of non-homologous end joining. Milder phenotypic expression of retinoblastoma was observed in patients with deletions larger than 1 Mb, which contained the MED4 gene. Clinical features were compared between patients with small (within 13q14), medium (within 13q12.3q21.2) and large (within 13q12q31.2) deletions. Patients with a small deletion can show macrocephaly, tall stature, obesity, motor and/or speech delay. Patients with a medium deletion show characteristic facial features, mild to moderate psychomotor delay, short stature and microcephaly. Patients with a large deletion have characteristic craniofacial dysmorphism, short stature, microcephaly, mild to severe psychomotor delay, hypotonia, constipation and feeding problems. Additional features included deafness, seizures and brain and heart anomalies. We found no correlation between clinical features and parental origin of the deletion. Our data suggest that hemizygous loss of NUFIP1 and PCDH8 may contribute to psychomotor delay, deletion of MTLR1 to microcephaly and loss of EDNRB to feeding difficulties and deafness.

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“…Conditional knockout mice revealed pRb roles in neural migration and neurogenesis during development and adulthood (Andrusiak et al., 2011, Ghanem et al., 2012). In humans, deletions in chromosome 13q including RB1 were associated with brain abnormalities (Mitter et al., 2011, Rodjan et al., 2010), suggesting that it can play a role in human nervous system development.…”

Section: Introductionmentioning

confidence: 99%

Modeling Developmental and Tumorigenic Aspects of Trilateral Retinoblastoma via Human Embryonic Stem Cells

et al. 2017

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SummaryHuman embryonic stem cells (hESCs) provide a platform for studying human development and understanding mechanisms underlying diseases. Retinoblastoma-1 (RB1) is a key regulator of cell cycling, of which biallelic inactivation initiates retinoblastoma, the most common congenital intraocular malignancy. We developed a model to study the role of RB1 in early development and tumor formation by generating RB1-null hESCs using CRISPR/Cas9. RB1−/− hESCs initiated extremely large teratomas, with neural expansions similar to those of trilateral retinoblastoma tumors, in which retinoblastoma is accompanied by intracranial neural tumors. Teratoma analysis further revealed a role for the transcription factor ZEB1 in RB1-mediated ectoderm differentiation. Furthermore, RB1−/− cells displayed mitochondrial dysfunction similar to poorly differentiated retinoblastomas. Screening more than 100 chemotherapies revealed an RB1–/–-specific cell sensitivity to carboplatin, exploiting their mitochondrial dysfunction. Together, our work provides a human pluripotent cell model for retinoblastoma and sheds light on developmental and tumorigenic roles of RB1.

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Brain Abnormalities on MR Imaging in Patients with Retinoblastoma

Cited by 32 publications

References 26 publications

RB controls growth, survival, and neuronal migration in human cerebral organoids

RB controls growth, survival, and neuronal migration in human cerebral organoids

Genotype–phenotype correlations in patients with retinoblastoma and interstitial 13q deletions

Modeling Developmental and Tumorigenic Aspects of Trilateral Retinoblastoma via Human Embryonic Stem Cells

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