Expression of Sonic Hedgehog During Cell Proliferation in the Human Cerebellum

Haldipur, Parthiv; Bharti, Upasna; Govindan, Subashika; Sarkar, Chitra; Iyengar, Soumya; Gressèns, Pierre; Mani, Shyamala

doi:10.1089/scd.2011.0206

Cited by 49 publications

(48 citation statements)

References 35 publications

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“…Body mass was reduced 19% in female mice and 23% in male Atg5 ShhCre mice compared with WT littermates at this age (female mice: P = 0.0013 [n = 6-8]; male mice: P = 0.0005 [n = 5-10]) ( Figure E3F). These phenotypes, which are consistent with the reported expression pattern of Shh in lung, neural, and intestinal epithelial cells (29)(30)(31), precluded analyses of animals older than 16 months in this study.…”

Section: Analyses Of Mice In Which Atg5supporting

confidence: 74%

Reserve Autophagic Capacity in Alveolar Epithelia Provides a Replicative Niche for Influenza A Virus

Hahn

Na²,

Weaver³

2014

Am J Respir Cell Mol Biol

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Autophagy contributes to cellular homeostasis through metabolite recycling and degradation of cytotoxic protein aggregates and damaged organelles. Although recent studies have established that the requirement for basal autophagy is largely tissue specific, the importance of autophagy for alveolar epithelial cell homeostasis remains an important knowledge gap. In the present study we generated two mouse models, with > 90% or > 50% recombination at the Atg5 locus in the distal respiratory epithelium, to assess the effect of dose-dependent decreases in autophagy on alveolar homeostasis. A 90% decrease in autophagy was well tolerated in young adult mice but resulted in alveolar septal thickening and altered lung mechanics in aged animals, consistent with accumulation of damage over time. By comparison, a 50% decrease in autophagy had no effect on alveolar structure or function throughout the murine life span, indicating that basal autophagy in this compartment exceeds that required for homeostasis. A 50% decrease in autophagy in the bronchoalveolar epithelium significantly attenuated influenza A/H3N2 viral replication, leading to improved lung structure and function and reduced morbidity and mortality after infection. The reserve of autophagic capacity in the alveolar epithelium may provide a niche for replication of influenza A virus.

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Section: Analyses Of Mice In Which Atg5supporting

confidence: 74%

Reserve Autophagic Capacity in Alveolar Epithelia Provides a Replicative Niche for Influenza A Virus

Hahn

Na²,

Weaver³

2014

Am J Respir Cell Mol Biol

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“…Although we were not able to detect the expression of SHH in PCs before 17 gw, we observed that GCPs expressed GLI1 at all stages analyzed (Fig. 3B), suggesting that an additional source of SHH might exist before 17 gw (32,33). However, SHH mRNA expression detected in the PCs from 17 gw coincides with a peak in GCP proliferation (Figs.…”

Section: Gcp Proliferation Is Similar In Cerebellar Vermis and Hemispmentioning

confidence: 81%

Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome

Aguilar

Meunier

Strehl

et al. 2012

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

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Joubert syndrome (JS) and Meckel syndrome (MKS) are pleiotropic ciliopathies characterized by severe defects of the cerebellar vermis, ranging from hypoplasia to aplasia. Interestingly, ciliary conditional mutant mice have a hypoplastic cerebellum in which the proliferation of cerebellar granule cell progenitors (GCPs) in response to Sonic hedgehog (SHH) is severely reduced. This suggests that Shh signaling defects could contribute to the vermis hypoplasia observed in the human syndromes. As existing JS/MKS mutant mouse models suggest apparently contradictory hypotheses on JS/MKS etiology, we investigated Shh signaling directly on human fetal samples. First, in an examination of human cerebellar development, we linked the rates of GCP proliferation to the different levels and localizations of active Shh signaling and showed that the GCP possessed a primary cilium with CEP290 at its base. Second, we found that the proliferation of GCPs and their response to SHH were severely impaired in the cerebellum of subjects with JS/MKS and Jeune syndrome. Finally, we showed that the defect in GCP proliferation was similar in the cerebellar vermis and hemispheres in all patients with ciliopathy analyzed, suggesting that the specific cause of vermal hypo-/aplasia precedes this defect. Our results, obtained from the analysis of human samples, show that the hemispheres and the vermis are affected in JS/MKS and provide evidence of a defective cellular mechanism in these pathologic processes.cilia | granular neuron | hindbrain | developmental pathology J oubert syndrome (JS; Online Mendelian Inheritance in Man no. 213300) and Meckel syndrome (MKS; Online Mendelian Inheritance in Man no. 249000) are believed to represent the two extremes of the same multisystemic disorder. JS is characterized by a complex malformation of the cerebellum/brainstem, the most striking feature of which is hypoplasia or complete aplasia of the cerebellar vermis (1, 2). In MKS, which is lethal in utero, this defect is associated with occipital encephalocele or anencephaly, severely cystic kidneys, and abnormal liver and skeleton. To date, 16 genes responsible for JS (NPHP1, AHI1, ARL13B, INPP5E, KIF7, OFD1, TCTN1, and CEP41), MKS (MKS1, B9D1, and B9D2), or both (RPGRIP1L, CEP290, CC2D2A, TMEM216, TMEM67/MKS3, and TCTN2) have been identified (3-6). Although all JS/MKS genes encode a ciliary/basal body (BB) protein, which is compelling evidence that the primary cilium is involved in these pathologic conditions, the cellular mechanisms by which cilium dysfunction leads to severe brain malformations remain a mystery.Because the use of human subjects to study human pathologies is problematic, insight into diseases usually comes from the analysis of murine models. However, none of the currently available murine models of JS/MKS faithfully recapitulate the cerebellar phenotype seen in JS/MKS. Interestingly, in ciliary conditional mutant mice, the cerebellum is hypoplastic and Sonic hedgehog (Shh)-dependent proliferation of granule cell progenitors (GCPs) is sev...

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“…Mid-sagittal cryo-sections of the cerebellum at 11 microns were taken. H&E staining and immunohistochemistry were performed as described previously 38 . Briefly, cryosections were incubated at room temperature for 1 hour after which they were subjected to heat-mediated antigen retrieval.…”

Section: Methodsmentioning

confidence: 99%

Active medulloblastoma enhancers reveal subgroup-specific cellular origins

Lin

Erkek

Tong

et al. 2016

Nature

Self Cite

322

358

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Summary Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Using H3K27ac and BRD4 ChIP-Seq, coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-Seq, that are responsible for subgroup divergence and implicate candidate cells-of-origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.

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Expression of Sonic Hedgehog During Cell Proliferation in the Human Cerebellum

Cited by 49 publications

References 35 publications

Reserve Autophagic Capacity in Alveolar Epithelia Provides a Replicative Niche for Influenza A Virus

Reserve Autophagic Capacity in Alveolar Epithelia Provides a Replicative Niche for Influenza A Virus

Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome

Active medulloblastoma enhancers reveal subgroup-specific cellular origins

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