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Dorsoventral patterning of the Xenopus eye involves differential temporal changes in the response of optic stalk and retinal progenitors to Hh signalling.

Wang X, Lupo G, He R, Barsacchi G, Harris WA, Liu Y - Neural Dev (2015)

Bottom Line: In loss-of-function assays, inhibition of Hh signalling starting from neurula stages caused expansion of the dorsal retina at the expense of the ventral retina and the optic stalk, while the effects of Hh inhibition during optic vesicle stages were limited to the reduction of optic stalk size.Our results suggest the existence of two competence windows during which the Hh pathway differentially controls patterning of the eye region.We speculate that this temporal regulation is important to coordinate dorsoventral patterning with morphogenesis and differentiation processes during eye development.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China. 13522764597@163.com.

ABSTRACT

Background: Hedgehog (Hh) signals are instrumental to the dorsoventral patterning of the vertebrate eye, promoting optic stalk and ventral retinal fates and repressing dorsal retinal identity. There has been limited analysis, however, of the critical window during which Hh molecules control eye polarity and of the temporal changes in the responsiveness of eye cells to these signals.

Results: In this study, we used pharmacological and molecular tools to perform stage-specific manipulations of Hh signalling in the developing Xenopus eye. In gain-of-function experiments, most of the eye was sensitive to ventralization when the Hh pathway was activated starting from gastrula/neurula stages. During optic vesicle stages, the dorsal eye became resistant to Hh-dependent ventralization, but this pathway could partially upregulate optic stalk markers within the retina. In loss-of-function assays, inhibition of Hh signalling starting from neurula stages caused expansion of the dorsal retina at the expense of the ventral retina and the optic stalk, while the effects of Hh inhibition during optic vesicle stages were limited to the reduction of optic stalk size.

Conclusions: Our results suggest the existence of two competence windows during which the Hh pathway differentially controls patterning of the eye region. In the first window, between the neural plate and the optic vesicle stages, Hh signalling exerts a global influence on eye dorsoventral polarity, contributing to the specification of optic stalk, ventral retina and dorsal retinal domains. In the second window, between optic vesicle and optic cup stages, this pathway plays a more limited role in the maintenance of the optic stalk domain. We speculate that this temporal regulation is important to coordinate dorsoventral patterning with morphogenesis and differentiation processes during eye development.

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Proposed model of the stage dependent effects of Hh signalling in the DV patterning of theXenopuseye. (A) During gastrula/neurula stages of development, Hh signalling controls the specification of both the OS and VR domains by promoting expression of OS (Pax2, Vax1b) and VR (Vax2) genes and repressing expression of DR genes (Tbx3, Tbx5). (B) During optic vesicle stages, the expression domains of Vax2 and Tbx3/5 become less dependent on Hh signalling (dashed lines), which is required to maintain Pax2 and Vax1b expression and proper OS development. At both stages, activation of Hh signalling is likely to depend on the Shh ligand, acting through inhibition of Gli repressor proteins (Gli-R) and increase of Gli activator proteins (Gli-A) [40]. Vax2 was previously shown to self-activate its own expression at optic vesicle stages [29].
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Fig7: Proposed model of the stage dependent effects of Hh signalling in the DV patterning of theXenopuseye. (A) During gastrula/neurula stages of development, Hh signalling controls the specification of both the OS and VR domains by promoting expression of OS (Pax2, Vax1b) and VR (Vax2) genes and repressing expression of DR genes (Tbx3, Tbx5). (B) During optic vesicle stages, the expression domains of Vax2 and Tbx3/5 become less dependent on Hh signalling (dashed lines), which is required to maintain Pax2 and Vax1b expression and proper OS development. At both stages, activation of Hh signalling is likely to depend on the Shh ligand, acting through inhibition of Gli repressor proteins (Gli-R) and increase of Gli activator proteins (Gli-A) [40]. Vax2 was previously shown to self-activate its own expression at optic vesicle stages [29].

Mentions: Hh signalling has a pivotal role in the specification of ventral positional identities in the eye. Overexpression experiments in zebrafish, Xenopus and chick embryos all caused expansion of OS and/or VR at the expense of DR [12,17,18,20], while zebrafish and mouse mutants for the Hh ligand Shh or the Hh pahway component Smo showed loss of ventral eye structures [13,18,19]. Here, we show that Hh signalling differentially controls eye DV patterning during two distinct temporal windows, one from the neurula to the optic vesicle stages and the other from the optic vesicle to the optic cup stages, respectively (FigureĀ 7). During the earlier window, most of the eye field region was competent to ventralization by the Hedgehog pathway. We noticed, however, that Hh signalling could upregulate ventral eye genes more efficiently than it could downregulate dorsal eye genes. For example, effective repression of dorsal genes required stronger treatment conditions than those sufficient to expand ventral gene expression domains. Moreover, ventralization of dorsal eye tissue in response to increased Hh signalling was often incomplete, as indicated by partial overlap of ectopic ventral gene expression with areas retaining expression of dorsal genes. These observations suggest that Hh signalling may regulate ventral and dorsal eye genes independently of each other. While ventral genes appear to be highly responsive to Hh pathway activation, repression of dorsal genes may involve additional mechanisms, such as interactions between Hh and other ventralizing signals [12] and/or inhibition of BMP signalling [14-16,26]. Following this earlier window, our results suggest that during formation of the optic vesicle, DR, VR and OS progenitors differentially modify their responsiveness to Hh signalling. In particular, the presumptive DR loses competence to Hh-dependent ventralization, VR progenitors maintain their fates in spite of reduced Hh signalling, but they retain competence to acquire OS fates in response to increased Hh signalling, and OS progenitors continue to rely on active Hh signalling to maintain their identity.Figure 7


Dorsoventral patterning of the Xenopus eye involves differential temporal changes in the response of optic stalk and retinal progenitors to Hh signalling.

Wang X, Lupo G, He R, Barsacchi G, Harris WA, Liu Y - Neural Dev (2015)

Proposed model of the stage dependent effects of Hh signalling in the DV patterning of theXenopuseye. (A) During gastrula/neurula stages of development, Hh signalling controls the specification of both the OS and VR domains by promoting expression of OS (Pax2, Vax1b) and VR (Vax2) genes and repressing expression of DR genes (Tbx3, Tbx5). (B) During optic vesicle stages, the expression domains of Vax2 and Tbx3/5 become less dependent on Hh signalling (dashed lines), which is required to maintain Pax2 and Vax1b expression and proper OS development. At both stages, activation of Hh signalling is likely to depend on the Shh ligand, acting through inhibition of Gli repressor proteins (Gli-R) and increase of Gli activator proteins (Gli-A) [40]. Vax2 was previously shown to self-activate its own expression at optic vesicle stages [29].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4373414&req=5

Fig7: Proposed model of the stage dependent effects of Hh signalling in the DV patterning of theXenopuseye. (A) During gastrula/neurula stages of development, Hh signalling controls the specification of both the OS and VR domains by promoting expression of OS (Pax2, Vax1b) and VR (Vax2) genes and repressing expression of DR genes (Tbx3, Tbx5). (B) During optic vesicle stages, the expression domains of Vax2 and Tbx3/5 become less dependent on Hh signalling (dashed lines), which is required to maintain Pax2 and Vax1b expression and proper OS development. At both stages, activation of Hh signalling is likely to depend on the Shh ligand, acting through inhibition of Gli repressor proteins (Gli-R) and increase of Gli activator proteins (Gli-A) [40]. Vax2 was previously shown to self-activate its own expression at optic vesicle stages [29].
Mentions: Hh signalling has a pivotal role in the specification of ventral positional identities in the eye. Overexpression experiments in zebrafish, Xenopus and chick embryos all caused expansion of OS and/or VR at the expense of DR [12,17,18,20], while zebrafish and mouse mutants for the Hh ligand Shh or the Hh pahway component Smo showed loss of ventral eye structures [13,18,19]. Here, we show that Hh signalling differentially controls eye DV patterning during two distinct temporal windows, one from the neurula to the optic vesicle stages and the other from the optic vesicle to the optic cup stages, respectively (FigureĀ 7). During the earlier window, most of the eye field region was competent to ventralization by the Hedgehog pathway. We noticed, however, that Hh signalling could upregulate ventral eye genes more efficiently than it could downregulate dorsal eye genes. For example, effective repression of dorsal genes required stronger treatment conditions than those sufficient to expand ventral gene expression domains. Moreover, ventralization of dorsal eye tissue in response to increased Hh signalling was often incomplete, as indicated by partial overlap of ectopic ventral gene expression with areas retaining expression of dorsal genes. These observations suggest that Hh signalling may regulate ventral and dorsal eye genes independently of each other. While ventral genes appear to be highly responsive to Hh pathway activation, repression of dorsal genes may involve additional mechanisms, such as interactions between Hh and other ventralizing signals [12] and/or inhibition of BMP signalling [14-16,26]. Following this earlier window, our results suggest that during formation of the optic vesicle, DR, VR and OS progenitors differentially modify their responsiveness to Hh signalling. In particular, the presumptive DR loses competence to Hh-dependent ventralization, VR progenitors maintain their fates in spite of reduced Hh signalling, but they retain competence to acquire OS fates in response to increased Hh signalling, and OS progenitors continue to rely on active Hh signalling to maintain their identity.Figure 7

Bottom Line: In loss-of-function assays, inhibition of Hh signalling starting from neurula stages caused expansion of the dorsal retina at the expense of the ventral retina and the optic stalk, while the effects of Hh inhibition during optic vesicle stages were limited to the reduction of optic stalk size.Our results suggest the existence of two competence windows during which the Hh pathway differentially controls patterning of the eye region.We speculate that this temporal regulation is important to coordinate dorsoventral patterning with morphogenesis and differentiation processes during eye development.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China. 13522764597@163.com.

ABSTRACT

Background: Hedgehog (Hh) signals are instrumental to the dorsoventral patterning of the vertebrate eye, promoting optic stalk and ventral retinal fates and repressing dorsal retinal identity. There has been limited analysis, however, of the critical window during which Hh molecules control eye polarity and of the temporal changes in the responsiveness of eye cells to these signals.

Results: In this study, we used pharmacological and molecular tools to perform stage-specific manipulations of Hh signalling in the developing Xenopus eye. In gain-of-function experiments, most of the eye was sensitive to ventralization when the Hh pathway was activated starting from gastrula/neurula stages. During optic vesicle stages, the dorsal eye became resistant to Hh-dependent ventralization, but this pathway could partially upregulate optic stalk markers within the retina. In loss-of-function assays, inhibition of Hh signalling starting from neurula stages caused expansion of the dorsal retina at the expense of the ventral retina and the optic stalk, while the effects of Hh inhibition during optic vesicle stages were limited to the reduction of optic stalk size.

Conclusions: Our results suggest the existence of two competence windows during which the Hh pathway differentially controls patterning of the eye region. In the first window, between the neural plate and the optic vesicle stages, Hh signalling exerts a global influence on eye dorsoventral polarity, contributing to the specification of optic stalk, ventral retina and dorsal retinal domains. In the second window, between optic vesicle and optic cup stages, this pathway plays a more limited role in the maintenance of the optic stalk domain. We speculate that this temporal regulation is important to coordinate dorsoventral patterning with morphogenesis and differentiation processes during eye development.

Show MeSH
Related in: MedlinePlus