BMP signaling suppresses Gemc1 expression and ependymal differentiation of mouse telencephalic progenitors

The lateral ventricles of the adult mammalian brain are lined by a single layer of multiciliated ependymal cells, which generate a flow of cerebrospinal fluid through directional beating of their cilia as well as regulate neurogenesis through interaction with adult neural stem cells. Ependymal cells are derived from a subset of embryonic neural stem-progenitor cells (NPCs, also known as radial glial cells) that becomes postmitotic during the late embryonic stage of development. Members of the Geminin family of transcriptional regulators including GemC1 and Mcidas play key roles in the differentiation of ependymal cells, but it remains largely unclear what extracellular signals regulate these factors and ependymal differentiation during embryonic and early-postnatal development. We now show that the levels of Smad1/5/8 phosphorylation and Id1/4 protein expression—both of which are downstream events of bone morphogenetic protein (BMP) signaling—decline in cells of the ventricular-subventricular zone in the mouse lateral ganglionic eminence in association with ependymal differentiation. Exposure of postnatal NPC cultures to BMP ligands or to a BMP receptor inhibitor suppressed and promoted the emergence of multiciliated ependymal cells, respectively. Moreover, treatment of embryonic NPC cultures with BMP ligands reduced the expression level of the ependymal marker Foxj1 and suppressed the emergence of ependymal-like cells. Finally, BMP ligands reduced the expression levels of Gemc1 and Mcidas in postnatal NPC cultures, whereas the BMP receptor inhibitor increased them. Our results thus implicate BMP signaling in suppression of ependymal differentiation from NPCs through regulation of Gemc1 and Mcidas expression during embryonic and early-postnatal stages of mouse telencephalic development.

EPEN-31. SINGLE-CELL RNAseq OF CHILDHOOD EPENDYMOMA REVEALS DISTINCT NEOPLASTIC CELL SUBPOPULATIONS THAT IMPACT ETIOLOGY, MOLECULAR CLASSIFICATION AND OUTCOME

Ependymoma (EPN) is a brain tumor commonly presenting in childhood that remains fatal in the majority of children. Intra-tumoral cellular heterogeneity in bulk-tumor samples significantly confounds our understanding of EPN biology, impeding development of effective therapy. We therefore used single-cell RNA sequencing to catalog cellular heterogeneity of 26 childhood EPN, predominantly from ST-RELA, PFA1 and PFA2 subgroups. ST-RELA and PFA subgroups clustered separately, with ST-RELA clustering largely according to individual sample-of-origin. PFA1 and PFA2 subgroup EPNs cells were intermixed and revealed 4 major subpopulations – 2 with characteristics of ependymal differentiation (transporter and ciliated phenotype subpopulations), an undifferentiated subpopulation and a mesenchymal phenotype. Pseudotime analysis showed the undifferentiated progenitor subpopulation either differentiating into ependymal differentiation subpopulations or transitioning into the mesenchymal subpopulation. Histological analysis revealed that undifferentiated and mesenchymal subpopulations cells colocalized to perinecrotic/perivascular zones, the putative ependymoma stem cell niche. Deconvolution of PFA bulk transcriptome data showed that undifferentiated and mesenchymal subpopulations were associated with a poor prognosis; whereas the ciliated ependymal cell-differentiated subpopulation was associated with a good prognosis. In conflict with current distinct classification paradigms, the ratio of mesenchymal and ciliated subpopulations determined bulk-tumor subgroups assignment to PFA1 and PFA2 respectively. This atlas of EPN cellular heterogeneity provides an important advance in our understanding of EPN biology, identifying high-risk associated subpopulations for therapeutic targeting.

Intraocular Ependymoma With Blood-Filled Spaces: Neoplasm or a Reactive Process With Ependymal Differentiation—A Dilemma

Intraocular glial lesions are rare and include retinal gliosis, hamartomas, and astrocytomas and rarely ependymomas. Ependymomas are slow-growing glial tumors preferentially arising in the central nervous system (CNS), occasionally presenting at sites outside the CNS, with only 2 cases of primary retinal ependymoma reported till date. We report herein the third such case of a 20-year-old male who presented with a painful blind eye. The enucleated specimen showed presence of a glial tumor with cells arranged in sheets as well as few true rosettes and pseudo-rosettes and an immunohistochemical profile similar to a classical ependymoma at usual sites in the CNS. Additionally, the presence of blood-filled spaces and few proliferating blood vessels made it a diagnostic challenge. All retinal glial lesions are positive for GFAP and S100. Therefore, immunostaining for EMA as well as the MIB-1-labeling index maybe vital in differentiating ependymomas from other intraocular glial lesions.

Ependymoblastoma with cystic change in a child

Ependymoblastoma is a rare and devastating primitive neuroectodermal tumor with ependymal differentiation. This tumor occurs very early in life and shows rapid growth and a diffuse infiltration through the leptomeningeal space. This neoplasm is characterized by uniform neuroepithelial cells, multilayered ependymal rosettes, perivascular pseudorosettes, and numerous mitotic figures. In this article, the authors report on a 4-year-old girl who was diagnosed as having an ependymoblastoma with cystic change. After a series of laboratory and imaging examinations, the left frontal solid-cystic lesion was surgically excised. Histological examinations confirmed the diagnosis of ependymoblastoma. The patient's intracranial hypertension symptoms were alleviated, and postoperative chemotherapy was performed. At the 6-month follow-up visit, MRI demonstrated evidence of relapse, and the girl died of tumor recurrence 14 months after surgery. Databases (PubMed, MEDLINE, Embase, and Web of Science) were searched for relevant articles published from 1970 to 2012; 71 eligible cases of ependymoblastoma were obtained, and 42 provided complete clinical details. Prognosis of children with ependymoblastoma is poor, and data on clinical behavior and optimal treatment strategies are lacking, but sustained remissions have been achieved after multimodal treatment according to existing literature. In this report, the clinical and histopathological features and therapeutic options of this tumor are discussed in the light of the published data. Further studies, especially those examining multimodality therapy, are needed to improve survival of children with this rare malignant CNS tumor.