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Ribosomopathies: how a common root can cause a tree of pathologies.

Danilova N, Gazda HT - Dis Model Mech (2015)

Bottom Line: Phenotypes of ribosomopathies are mediated both by p53-dependent and -independent pathways.The current challenge is to identify differences in response to ribosomal stress that lead to specific tissue defects in various ribosomopathies.Here, we review recent findings in this field, with a particular focus on animal models, and discuss how, in some cases, the different phenotypes of ribosomopathies might arise from differences in the spatiotemporal expression of the affected genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA 90095, USA ndanilova@ucla.edu hanna.gazda@childrens.harvard.edu.

No MeSH data available.


Related in: MedlinePlus

Origin of developmental defects in RP-deficient zebrafish embryos. (A) ΔNp63 expression (black arrow, upper panels) in early zebrafish embryos defines the non-neural ectoderm field and overlaps with a marker of non-neural ectoderm, gata2 (black arrow, lower panels). In Rps19-deficient zebrafish [in which rps19 expression has been knocked down with a morpholino oligonucleotide (MO)], this field is expanded (right upper and lower panels). Staining with a probe for goosecoid (gsc), necessary for the formation of the dorsoventral axis of the embryo, marks the dorsal side (red arrow). Arrowheads point to the neural field. This is an in situ hybridization image at gastrulation, 80% epiboly (Box 1). Dorsal is to the right. wt, wild type. (B) Expression of pax2, which has a key role in the development of the CNS, eyes, urogenital tract and kidneys, is altered in Rps19-deficient zebrafish embryos. Arrows and arrowheads point, respectively, to forebrain and eye fields, which are contracted in Rps19-deficient embryos. This is an in situ hybridization image at 16 hpf. (C) Schematics showing how expansion of non-neural ectoderm in early zebrafish embryos leads to the contraction of the neural field, especially the area of the forebrain and eye. This research was originally published in Blood (Danilova et al., 2008b). © American Society of Hematology.
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DMM020529F4: Origin of developmental defects in RP-deficient zebrafish embryos. (A) ΔNp63 expression (black arrow, upper panels) in early zebrafish embryos defines the non-neural ectoderm field and overlaps with a marker of non-neural ectoderm, gata2 (black arrow, lower panels). In Rps19-deficient zebrafish [in which rps19 expression has been knocked down with a morpholino oligonucleotide (MO)], this field is expanded (right upper and lower panels). Staining with a probe for goosecoid (gsc), necessary for the formation of the dorsoventral axis of the embryo, marks the dorsal side (red arrow). Arrowheads point to the neural field. This is an in situ hybridization image at gastrulation, 80% epiboly (Box 1). Dorsal is to the right. wt, wild type. (B) Expression of pax2, which has a key role in the development of the CNS, eyes, urogenital tract and kidneys, is altered in Rps19-deficient zebrafish embryos. Arrows and arrowheads point, respectively, to forebrain and eye fields, which are contracted in Rps19-deficient embryos. This is an in situ hybridization image at 16 hpf. (C) Schematics showing how expansion of non-neural ectoderm in early zebrafish embryos leads to the contraction of the neural field, especially the area of the forebrain and eye. This research was originally published in Blood (Danilova et al., 2008b). © American Society of Hematology.

Mentions: Extra digits or phalanges are among the notable congenital defects observed in individuals with DBA (Halperin and Freedman, 1989) and in the Rpl24 mouse mutant (Oliver et al., 2004) (Fig. 1). As discussed above in the section devoted to the phenotypes of DBA patients and animal models, eye defects are also a common feature. The combination of these defects suggests that they might originate during development from a misbalance between neural and non-neural ectoderm in the early embryo. Development of non-neural ectoderm is controlled by a member of the p53 protein family, ΔNp63. Besides its role during development, ΔNp63 is a p53 target gene and is upregulated in response to p53 activation (Bourdon, 2007). In the gastrulating zebrafish embryos, ΔNp63 expression is localized to the ventral side of the embryo and marks non-neural ectoderm; its overexpression leads to the expansion of non-neural ectoderm and to the suppression of neural structures (Bakkers et al., 2002). Later in development ΔNp63 controls the development of limbs and its overactivity can lead to the duplication of limb structures (Mills et al., 1999). In Rps19-deficient zebrafish embryos, the area of ΔNp63 expression expands to the dorsal side (Danilova et al., 2008b) (Fig. 4A). This corresponds to the expansion of non-neural ectoderm into the neural field, as confirmed by hybridization with gata2, a marker of non-neural ectoderm (Fig. 4A). Shrinkage of the neural field affects mostly the forebrain and eyes, as illustrated by the expression of pax2, which has a key role in the development of the CNS, eyes, urogenital tract and kidneys (Krauss et al., 1991) (Fig. 4B,C).Fig. 4.


Ribosomopathies: how a common root can cause a tree of pathologies.

Danilova N, Gazda HT - Dis Model Mech (2015)

Origin of developmental defects in RP-deficient zebrafish embryos. (A) ΔNp63 expression (black arrow, upper panels) in early zebrafish embryos defines the non-neural ectoderm field and overlaps with a marker of non-neural ectoderm, gata2 (black arrow, lower panels). In Rps19-deficient zebrafish [in which rps19 expression has been knocked down with a morpholino oligonucleotide (MO)], this field is expanded (right upper and lower panels). Staining with a probe for goosecoid (gsc), necessary for the formation of the dorsoventral axis of the embryo, marks the dorsal side (red arrow). Arrowheads point to the neural field. This is an in situ hybridization image at gastrulation, 80% epiboly (Box 1). Dorsal is to the right. wt, wild type. (B) Expression of pax2, which has a key role in the development of the CNS, eyes, urogenital tract and kidneys, is altered in Rps19-deficient zebrafish embryos. Arrows and arrowheads point, respectively, to forebrain and eye fields, which are contracted in Rps19-deficient embryos. This is an in situ hybridization image at 16 hpf. (C) Schematics showing how expansion of non-neural ectoderm in early zebrafish embryos leads to the contraction of the neural field, especially the area of the forebrain and eye. This research was originally published in Blood (Danilova et al., 2008b). © American Society of Hematology.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4582105&req=5

DMM020529F4: Origin of developmental defects in RP-deficient zebrafish embryos. (A) ΔNp63 expression (black arrow, upper panels) in early zebrafish embryos defines the non-neural ectoderm field and overlaps with a marker of non-neural ectoderm, gata2 (black arrow, lower panels). In Rps19-deficient zebrafish [in which rps19 expression has been knocked down with a morpholino oligonucleotide (MO)], this field is expanded (right upper and lower panels). Staining with a probe for goosecoid (gsc), necessary for the formation of the dorsoventral axis of the embryo, marks the dorsal side (red arrow). Arrowheads point to the neural field. This is an in situ hybridization image at gastrulation, 80% epiboly (Box 1). Dorsal is to the right. wt, wild type. (B) Expression of pax2, which has a key role in the development of the CNS, eyes, urogenital tract and kidneys, is altered in Rps19-deficient zebrafish embryos. Arrows and arrowheads point, respectively, to forebrain and eye fields, which are contracted in Rps19-deficient embryos. This is an in situ hybridization image at 16 hpf. (C) Schematics showing how expansion of non-neural ectoderm in early zebrafish embryos leads to the contraction of the neural field, especially the area of the forebrain and eye. This research was originally published in Blood (Danilova et al., 2008b). © American Society of Hematology.
Mentions: Extra digits or phalanges are among the notable congenital defects observed in individuals with DBA (Halperin and Freedman, 1989) and in the Rpl24 mouse mutant (Oliver et al., 2004) (Fig. 1). As discussed above in the section devoted to the phenotypes of DBA patients and animal models, eye defects are also a common feature. The combination of these defects suggests that they might originate during development from a misbalance between neural and non-neural ectoderm in the early embryo. Development of non-neural ectoderm is controlled by a member of the p53 protein family, ΔNp63. Besides its role during development, ΔNp63 is a p53 target gene and is upregulated in response to p53 activation (Bourdon, 2007). In the gastrulating zebrafish embryos, ΔNp63 expression is localized to the ventral side of the embryo and marks non-neural ectoderm; its overexpression leads to the expansion of non-neural ectoderm and to the suppression of neural structures (Bakkers et al., 2002). Later in development ΔNp63 controls the development of limbs and its overactivity can lead to the duplication of limb structures (Mills et al., 1999). In Rps19-deficient zebrafish embryos, the area of ΔNp63 expression expands to the dorsal side (Danilova et al., 2008b) (Fig. 4A). This corresponds to the expansion of non-neural ectoderm into the neural field, as confirmed by hybridization with gata2, a marker of non-neural ectoderm (Fig. 4A). Shrinkage of the neural field affects mostly the forebrain and eyes, as illustrated by the expression of pax2, which has a key role in the development of the CNS, eyes, urogenital tract and kidneys (Krauss et al., 1991) (Fig. 4B,C).Fig. 4.

Bottom Line: Phenotypes of ribosomopathies are mediated both by p53-dependent and -independent pathways.The current challenge is to identify differences in response to ribosomal stress that lead to specific tissue defects in various ribosomopathies.Here, we review recent findings in this field, with a particular focus on animal models, and discuss how, in some cases, the different phenotypes of ribosomopathies might arise from differences in the spatiotemporal expression of the affected genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA 90095, USA ndanilova@ucla.edu hanna.gazda@childrens.harvard.edu.

No MeSH data available.


Related in: MedlinePlus