Retinoic acid and Cyp26b1 are critical regulators of osteogenesis in the axial skeleton

Spoorendonk, Kirsten M.; Peterson-Maduro, Josi; Renn, Jörg; Trowe, Torsten; Kranenbarg, S.; Winkler, Christoph; Schulte‐Merker, Stefan

doi:10.1242/dev.024034

Cited by 225 publications

(239 citation statements)

References 45 publications

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“…In a further study, the medaka promoter construct described here has also been used to generate transgenic zebrafish (Spoorendonk et al, 2008). Similar expression patterns of this transgene in the analyzed late larval zebrafish suggest that the regulatory control of osterix expression is conserved in both teleost species.…”

Section: Discussionmentioning

confidence: 78%

Osterix‐mCherry transgenic medaka for in vivo imaging of bone formation

Renn

Winkler

2008

Developmental Dynamics

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Intramembranous and chondral bone formation by osteoblasts is found in all vertebrates. The genetic network controlling osteoblast differentiation is highly conserved and regulated by a small number of key factors, including the zinc-finger transcription factor Osterix. Expression analysis of osterix in the teleost model medaka revealed a highly restricted expression in skeletal regions. For in vivo imaging, we generated transgenic medaka expressing mCherry under control of the osterix promoter. We show that the transgene becomes expressed in early osteoblasts, which have not yet mineralized bone matrix, and remains high in matured and mineralizing osteoblasts. Life imaging of transgenic larvae provided insight into the appearance and behavior of early osteoblasts during development of the teleost cranium, vertebrae, and caudal fin. In summary, osterix-mCherry transgenic medaka enable us to analyze osteoblasts during different maturation phases in vivo and represent a unique tool to study osteoblast behavior in vertebrate embryos and adults. Developmental Dynamics 238:241-248, 2009.

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Section: Discussionmentioning

confidence: 78%

Osterix‐mCherry transgenic medaka for in vivo imaging of bone formation

Renn

Winkler

2008

Developmental Dynamics

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119

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“…1A), two calcified structures with a different mineral composition from bone (15,16). Mutant embryos were viable when separated at 6 dpf from their siblings via alizarin redbased in vivo skeletal staining (17). Except for the absence of a mineralized skeleton (Fig.…”

Section: Resultsmentioning

confidence: 99%

Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish

Huitema

Apschner

Logister

et al. 2012

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

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100

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Bone mineralization is an essential step during the embryonic development of vertebrates, and bone serves vital functions in human physiology. To systematically identify unique gene functions essential for osteogenesis, we performed a forward genetic screen in zebrafish and isolated a mutant, no bone (nob), that does not form any mineralized bone. Positional cloning of nob identified the causative gene to encode ectonucleoside triphosphate/ diphosphohydrolase 5 (entpd5); analysis of its expression pattern demonstrates that entpd5 is specifically expressed in osteoblasts. An additional mutant, dragonfish (dgf), exhibits ectopic mineralization in the craniofacial and axial skeleton and encodes a loss-offunction allele of ectonucleotide pyrophosphatase phosphodiesterase 1 (enpp1). Intriguingly, generation of double-mutant nob/ dgf embryos restored skeletal mineralization in nob mutants, indicating that mechanistically, Entpd5 and Enpp1 act as reciprocal regulators of phosphate/pyrophosphate homeostasis in vivo. Consistent with this, entpd5 mutant embryos can be rescued by high levels of inorganic phosphate, and phosphate-regulating factors, such as fgf23 and npt2a, are significantly affected in entpd5 mutant embryos. Our study demonstrates that Entpd5 represents a previously unappreciated essential player in phosphate homeostasis and skeletal mineralization.

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“…Because of their ability to metabolize RA, CYP26 enzymes are believed to exert local control of RA synthesis and seem to play a critical role during ontogenesis. 45 Bearing in mind the strong correlation of proteins facilitating retinol uptake (CRBP1) and activation (ALDH1A1), as well as RA degradation (CYP26B1) (see Supplemental Figure S8B at http://ajp. amjpathol.org), it can be assumed that elevated CYP26B1 expression in glial tumors indirectly mirrors elevated RA synthesis, resulting as physiological response to control elevated intracellular RA concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…amjpathol.org), it can be assumed that elevated CYP26B1 expression in glial tumors indirectly mirrors elevated RA synthesis, resulting as physiological response to control elevated intracellular RA concentrations. 24,45 It is further conceivable that, in the absence of CRABP2, high levels of CRABP1, CYP26B1, and FABP5 greatly reduce the likelihood of RA reaching its designated nuclear receptor and inducing differentiation without being degraded or diverted into an alternative signaling pathway first. Nonetheless, despite these alluring speculations, further studies would be needed to corroborate these hypotheses.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

Campos

Centner

Bermejo

et al. 2011

The American Journal of Pathology

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Undifferentiated cell populations may influence tumor growth in malignant glioma. We investigated potential disruptions in the retinoic acid (RA) differentiation pathway that could lead to a loss of differentiation capacity, influencing patient prognosis. Expression of key molecules belonging to the RA differentiation pathway was analyzed in 283 astrocytic gliomas and was correlated with tumor proliferation, tumor differentiation, and patient survival. In addition, in situ concentrations of retinoids were measured in tumors, and RA signaling events were studied in vitro. Unlike other tumors, in gliomas expression of most RA signaling molecules increased with malignancy and was associated with augmented intratumoral retinoid levels in high-grade gliomas. Aberrantly expressed RA signaling molecules included i) the retinol-binding protein CRBP1, which facilitates cellular retinoid uptake; ii) ALDH1A1, capable of activating RA precursors; iii) the RA-degrading enzyme CYP26B1; and iv) the RA-binding protein FABP5, which can inhibit RA-induced differentiation. In contrast, expression of the RA-binding protein CRABP2, which fosters differentiation, was decreased in high-grade tumors. Moreover, expression of CRBP1 correlated with tumor proliferation, and FABP5 expression correlated with an undifferentiated tumor phenotype. CRBP1 and ALDH1A1 were independent prognostic markers for adverse patient survival. Our data indicate a complex and clinically relevant deregulation of RA signaling, which seems to be a central event in glioma pathogenesis.

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Retinoic acid and Cyp26b1 are critical regulators of osteogenesis in the axial skeleton

Cited by 225 publications

References 45 publications

Osterix‐mCherry transgenic medaka for in vivo imaging of bone formation

Osterix‐mCherry transgenic medaka for in vivo imaging of bone formation

Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

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