SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity

Schell-Apacik, Can; Rivero, Mariel; Knepper, Jessica L.; Roessler, Erich; Muenke, Maximilian; Ming, Jeffrey E.

doi:10.1007/s00439-003-0950-4

Cited by 38 publications

(16 citation statements)

References 54 publications

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“…Especially SHH has been implicated as central in the process of determining the identity of the progenitor cells of the spinal cord. Mutations of SHH in human have been noted as causative of holoprosencephaly (Roessler et al, 1996) and also to impair neural patterning activity (Schell-Apacik et al, 2003). The intensity levels of SHH were below the detection limit on the gene chips, and thus we were not able to deduce any changes in expression between the LCCS patients and controls.…”

Section: Discussionmentioning

confidence: 78%

Indicative oligodendrocyte dysfunction in spinal cords of human fetuses suffering from a lethal motoneuron disease

et al. 2005

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Human spinal cord development is still poorly understood and detailed molecular analyses of human motoneuron diseases could improve our understanding of the normal developmental processes of the spinal cord. Lethal Congenital Contracture Syndrome (LCCS, MIM 253310) provides a human model to study the early motoneuronal development. A typical phenotype of LCCS fetuses consists of multiple joint contractures, distinct facial features, and hydrops. Tissue pathology is characterized by severe muscle atrophy, lung hypoplasia, and degeneration of the anterior horn of the spinal cord as the hallmark of the syndrome. In this study we performed a global transcript analysis of LCCS spinal cords. The RNA expression profiles of these spinal cords were compared to age-matched healthy control fetuses, aborted for nonrelated causes. In addition, we applied phylogenetic footprinting methods to decipher the mechanisms of transcriptional regulation in the affected transcripts. Changes in transcripts involved with the development of the CNS and oligodendrocytes were obvious and the transcription factor PAX6 was identified as a key regulator during spinal cord development. In addition, transcript pathway analysis clearly indicated genes belonging to groups with neuronal functions to be affected. Our findings support the hypothesis that human motoneurons and oligodendrocytes are dependent on each other during their development and are influenced by distinct transcription factors previously known to act during murine and chick motoneuron development. These data provide valuable information about the molecular pathways putatively active in motoneuron diseases.

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Section: Discussionmentioning

confidence: 78%

Indicative oligodendrocyte dysfunction in spinal cords of human fetuses suffering from a lethal motoneuron disease

et al. 2005

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“…Expression of Shh has been reported in human embryonic ventral spinal cord and mesencephalon (Hajihosseini et al, 1996; Orentas et al, 1999), and Shh mutation is related to brain defects such as holoprosencephaly or cyclopia (Schell-Apacik et al, 2003). Experimentally, these defects can be induced by the selective Shh inhibitor cyclopamine, a steroidal alkaloid known to interrupt Shh signaling by binding to its co-receptor Smoothened (Incardona et al, 1998).…”

Section: Resultsmentioning

confidence: 99%

Sonic hedgehog promotes generation and maintenance of human forebrain Olig2 progenitors

Ortega

Radonjic

Zečević

2013

Front. Cell. Neurosci.

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Function of oligodendrocytes (OLs), myelin forming cells in the CNS, is disrupted in demyelinating diseases such as periventricular leukomalacia or multiple sclerosis. It is, thus, important to better understand factors that can affect generation or differentiation of human OLs. In rodents, Sonic hedgehog (Shh) is influencing expression of Olig2, a helix-loop-helix transcription factor required for development of OLs. In humans, Olig2 is present in cortical progenitors at midgestation, however the role of Shh in the specification of human OLs, including Olig2 positive (Olig2+) progenitors, is not fully understood. Here we studied in vitro effects of Shh signaling on proliferation and specification of human cortical Olig2+ progenitors at midgestation. First, we established that the spatial pattern of Olig2 expression in the human developing CNS, described on cryosections, was preserved in mixed and enriched radial glia cell (RGC) cultures. Next, we demonstrated that in vitro treatment with Shh induced an increase in the number of Olig2+ progenitors. Shh treatment increased the density of early oligodendrocyte progenitors (OPCs) at the expense of RGC, while the number of late OPCs, did not change. However, inhibition of endogenous Shh with cyclopamine did not reduce the density of Olig2+ cells, implying the presence of an additional Shh-independent mechanism for OLs generation in vitro. These results suggest that the primary role of Shh signaling in the human dorsal oligodendrogenesis is the expansion and specification of multipotent radial glia progenitors into Olig2+ early OPCs. These results obtained in vitro are relevant to understand primary myelination during CNS development, as well as remyelination in demyelinating diseases.

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“…Similar to Shh [59], mutations in the homeodomain of the human Six3 gene cause holoprosencephaly and are associated with midline facial cleft - tessier cleft 14 [60]. In mice, it has been shown that Six3 protein increases expression of Ccnd1 protein [61], which is directly related to TGFβ signaling (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Systematic analysis of palatal transcriptome to identify cleft palate genes within TGFβ3-knockout mice alleles: RNA-Seq analysis of TGFβ3 Mice

Öztürk

Zhu

et al. 2013

BMC Genomics

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BackgroundIn humans, cleft palate (CP) accounts for one of the largest number of birth defects with a complex genetic and environmental etiology. TGFβ3 has been established as an important regulator of palatal fusion in mice and it has been shown that TGFβ3-null mice exhibit CP without any other major deformities. However, the genes that regulate cellular decisions and molecular mechanisms maintained by the TGFβ3 pathway throughout palatogenesis are predominantly unexplored. Our objective in this study was to analyze global transcriptome changes within the palate during different gestational ages within TGFβ3 knockout mice to identify TGFβ3-associated genes previously unknown to be associated with the development of cleft palate. We used deep sequencing technology, RNA-Seq, to analyze the transcriptome of TGFβ3 knockout mice at crucial stages of palatogenesis, including palatal growth (E14.5), adhesion (E15.5), and fusion (E16.5).ResultsThe overall transcriptome analysis of TGFβ3 wildtype mice (C57BL/6) reveals that almost 6000 genes were upregulated during the transition from E14.5 to E15.5 and more than 2000 were downregulated from E15.5 to E16.5. Using bioinformatics tools and databases, we identified the most comprehensive list of CP genes (n = 322) in which mutations cause CP either in humans or mice, and analyzed their expression patterns. The expression motifs of CP genes between TGFβ3+/− and TGFβ3−/− were not significantly different from each other, and the expression of the majority of CP genes remained unchanged from E14.5 to E16.5. Using these patterns, we identified 8 unique genes within TGFβ3−/− mice (Chrng, Foxc2, H19, Kcnj13, Lhx8, Meox2, Shh, and Six3), which may function as the primary contributors to the development of cleft palate in TGFβ3−/− mice. When the significantly altered CP genes were overlaid with TGFβ signaling, all of these genes followed the Smad-dependent pathway.ConclusionsOur study represents the first analysis of the palatal transcriptome of the mouse, as well as TGFβ3 knockout mice, using deep sequencing methods. In this study, we characterized the critical regulation of palatal transcripts that may play key regulatory roles through crucial stages of palatal development. We identified potential causative CP genes in a TGFβ3 knockout model, which may lead to a better understanding of the genetic mechanisms of palatogenesis and provide novel potential targets for gene therapy approaches to treat cleft palate.

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SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity

Cited by 38 publications

References 54 publications

Indicative oligodendrocyte dysfunction in spinal cords of human fetuses suffering from a lethal motoneuron disease

Indicative oligodendrocyte dysfunction in spinal cords of human fetuses suffering from a lethal motoneuron disease

Sonic hedgehog promotes generation and maintenance of human forebrain Olig2 progenitors

Systematic analysis of palatal transcriptome to identify cleft palate genes within TGFβ3-knockout mice alleles: RNA-Seq analysis of TGFβ3 Mice

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