Embryonic expression of cholesterogenic genes is restricted to distinct domains and colocalizes with apoptotic regions in mice

Laubner, Daniela; Breitling, Rainer; Adamski, Jerzy

doi:10.1016/s0169-328x(03)00094-9

Cited by 19 publications

(15 citation statements)

References 29 publications

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“…3,4b,5a and 7b); long bones were not studied in the mice and the vertebrae and mandible were not studied in the humans. These expression profiles are generally consistent with prior studies in the mouse (Cunningham et al 2009;Laubner et al 2003).…”

Section: Hematopoietic Tissuessupporting

confidence: 90%

“…Understanding the relationship between NSDHL expression and disease requires extension of expression studies in mouse (Cunningham et al 2009;Laubner et al 2003;Liu et al 1999;Caldas et al 2005) to the human. Furthermore, while human NSDHL expression has been profiled previously within the CNS (McLarren et al 2010), human NSDHL expression in peripheral tissues has not been profiled.…”

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confidence: 99%

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Expression profile of NSDHL in human peripheral tissues

et al. 2011

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NAD(P) steroid dehydrogenase-like (NSDHL) is an X-linked gene that encodes a 3β-hydroxysteroid dehydrogenase in the cholesterol biosynthetic pathway. Loss-of-function mutations in NSDHL cause Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects (CHILD) and CK syndromes. CHILD syndrome is a male lethal X-linked dominant disorder characterized by asymmetric skin and limb anomalies in affected females. CK syndrome is an intellectual disability disorder characterized by disproportionate short stature, brain malformations, and dysmorphic features in affected males. To understand better the relationship of the expression of mRNA and protein encoded by human NSDHL to the peripheral malformations of these disorders, we characterized the peripheral expression of the mRNA and protein by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), immunoblotting and immunohistochemistry. We also profiled the mRNA expression of mouse Nsdhl by in situ hybridization. Expression of the mRNA and protein encoded by human NSDHL parallels that of mouse Nsdhl mRNA for most but not all tissues. Furthermore, human NSDHL protein and mouse Nsdhl mRNA were expressed in tissues synthesizing cholesterol and steroids and in all peripheral tissues affected by CHILD or CK syndromes.

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Section: Hematopoietic Tissuessupporting

confidence: 90%

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confidence: 99%

Expression profile of NSDHL in human peripheral tissues

et al. 2011

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“…Cholesterol is a key component of the Hedgehog signalling pathway that is essential for patterning the primitive gut tube (Harmon et al, 2002). Notably, the concerted changes of the cholesterol pathway genes are consistent with the concept that cholesterogenic enzymes constitute a synexpression group in embryos and cultured fibroblasts (Iyer et Laubner et al, 2003;Marijanovic et al, 2003). In the Sox17-null embryo, expression of Ihh in the gut endoderm and Ptch1 in the lateral plate mesoderm is down-regulated, indicating that loss of Sox17 function is associated with reduced Hedgehog signalling activity (Kanai-Azuma et al, 2002).…”

Section: Identification Of Sox17-dependent Changes In Gene Expressionsupporting

confidence: 73%

Sox17-dependent gene expression and early heart and gut development in Sox17-deficient mouse embryos

Pfister¹,

Jones²,

Power³

et al. 2011

Int. J. Dev. Biol.

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Sox17 is a transcription factor that is required for maintenance of the definitive endoderm in mouse embryos. By expression profiling of wild-type and mutant embryos and Sox17-overexpressing hepatoma cells, we identified genes with Sox17-dependent expression. Among the genes that were up-regulated in Sox17-null embryos and down-regulated by Sox17-expressing HepG2 cells is a set of genes that are expressed in the developing liver, suggesting that one function of Sox17 is the repression of liver gene expression, which is compatible with a role for Sox17 in maintaining the definitive endoderm in a progenitor state. Consistent with these findings, Sox17 -/-cells display a diminished capacity to contribute to the definitive endoderm when transplanted into wild-type hosts. Analysis of gene ontology further revealed that many genes related to heart development were downregulated in Sox17-null embryos. This is associated with the defective development of the heart in the mutant embryos, which is accompanied by localised loss of Myocd-expressing cardiogenic progenitors and the malformation of the anterior intestinal portal.

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“…Msx2 normally coincides with interdigital apoptosis during limb development (24), but in Prx1-Cre; POR lox/lox limb buds it is reduced except between digits 3 and 4, although why this space is spared is not clear. Interestingly, enzymes of cholesterol biosynthesis are regionally restricted in their expression during normal digital morphogenesis, e.g., HMG-CoA reductase expression becomes confined to interdigital zones which undergo apoptosis at E12.5 (48).…”

Section: Discussionmentioning

confidence: 99%

Cholesterol Metabolism: the Main Pathway Acting Downstream of Cytochrome P450 Oxidoreductase in Skeletal Development of the Limb

Schmidt

Hughes

Chudek

et al. 2009

Molecular and Cellular Biology

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Cytochrome P450 oxidoreductase (POR) is the obligate electron donor for all microsomal cytochrome P450 enzymes, which catalyze the metabolism of a wide spectrum of xenobiotic and endobiotic compounds. Point mutations in POR have been found recently in patients with Antley-Bixler-like syndrome, which includes limb skeletal defects. In order to study P450 function during limb and skeletal development, we deleted POR specifically in mouse limb bud mesenchyme. Forelimbs and hind limbs in conditional knockout (CKO) mice were short with thin skeletal elements and fused joints. POR deletion occurred earlier in forelimbs than in hind limbs, leading additionally to soft tissue syndactyly and loss of wrist elements and phalanges due to changes in growth, cell death, and skeletal segmentation. Transcriptional analysis of E12.5 mouse forelimb buds demonstrated the expression of P450s involved in retinoic acid, cholesterol, and arachidonic acid metabolism. Biochemical analysis of CKO limbs confirmed retinoic acid excess. In CKO limbs, expression of genes throughout the whole cholesterol biosynthetic pathway was upregulated, and cholesterol deficiency can explain most aspects of the phenotype. Thus, cellular POR-dependent cholesterol synthesis is essential during limb and skeletal development. Modulation of P450 activity could contribute to susceptibility of the embryo and developing organs to teratogenesis.

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Embryonic expression of cholesterogenic genes is restricted to distinct domains and colocalizes with apoptotic regions in mice

Cited by 19 publications

References 29 publications

Expression profile of NSDHL in human peripheral tissues

Expression profile of NSDHL in human peripheral tissues

Sox17-dependent gene expression and early heart and gut development in Sox17-deficient mouse embryos

Cholesterol Metabolism: the Main Pathway Acting Downstream of Cytochrome P450 Oxidoreductase in Skeletal Development of the Limb

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