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Nodal signaling is required for closure of the anterior neural tube in zebrafish.

Aquilina-Beck A, Ilagan K, Liu Q, Liang JO - BMC Dev. Biol. (2007)

Bottom Line: N-cadherin expression and localization to the membrane are reduced in fish that lack Nodal signaling.Overexpression of an activated form of the TGFbeta Type I receptor Taram-A (Taram-A*) cell autonomously rescues mesendoderm formation in fish with a severe decrease in Nodal signaling.This work helps establish a role for Nodal signals in neurulation, and suggests that defects in Nodal signaling could underlie human neural tube defects such as exencephaly, a fatal condition characterized by an open neural tube in the anterior brain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, USA. axa161@case.edu

ABSTRACT

Background: Nodals are secreted signaling proteins with many roles in vertebrate development. Here, we identify a new role for Nodal signaling in regulating closure of the rostral neural tube of zebrafish.

Results: We find that the neural tube in the presumptive forebrain fails to close in zebrafish Nodal signaling mutants. For instance, the cells that will give rise to the pineal organ fail to move from the lateral edges of the neural plate to the midline of the diencephalon. The open neural tube in Nodal signaling mutants may be due in part to reduced function of N-cadherin, a cell adhesion molecule expressed in the neural tube and required for neural tube closure. N-cadherin expression and localization to the membrane are reduced in fish that lack Nodal signaling. Further, N-cadherin mutants and morphants have a pineal phenotype similar to that of mutants with deficiencies in the Nodal pathway. Overexpression of an activated form of the TGFbeta Type I receptor Taram-A (Taram-A*) cell autonomously rescues mesendoderm formation in fish with a severe decrease in Nodal signaling. We find that overexpression of Taram-A* also corrects their open neural tube defect. This suggests that, as in mammals, the mesoderm and endoderm have an important role in regulating closure of the anterior neural tube of zebrafish.

Conclusion: This work helps establish a role for Nodal signals in neurulation, and suggests that defects in Nodal signaling could underlie human neural tube defects such as exencephaly, a fatal condition characterized by an open neural tube in the anterior brain.

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Correlation between an expanded or divided pineal and an open neural tube. (A-E) Lateral views of live embryos at 1 dpf, anterior to the left. (A) While the head of the WT embryo is smooth and rounded, (B) the head of the sqt embryo is pointed (arrow). (C-E) Higher magnification of the anterior embryo reveals variability in the brain morphology of sqt mutants. In (C) WT embryos and (D) some sqt mutants, the border between the tectum and tegmentum (open arrowheads) appears as a smooth, straight line. (E) However, in some sqt mutants the border appears to be abnormally shaped or indistinct (open arrowhead), suggesting that the morphology of tectum or tegmentum is perturbed. (F-J) Embryos were fixed at 1 dpf, and processed for in situ hybridization with antisense probes for the pineal gene otx5 and the dorsal neural tube gene wnt1. In (F) WT and (G) sqt embryos with a single, round pineal anlage, the wnt1 expressing cells (open arrowheads) form a single domain along the dorsal neural tube. In contrast, sqt embryos with an (H) elongated or (I-J) divided pineal anlage have two parallel lines of wnt1 expressing cells. (K-P) Embryos were fixed at 1 dpf, processed for in situ hybridization with an antisense probe for epha4a, and then either (K-N) imaged in dorsal view, anterior to the left or (O, P) cut through epha4a-expressing rhombomere 5 to bisect the embryo into anterior and posterior halves. The locations of the otic vesicles (o), rhombomere 5 (arrows), and midline (open arrowhead) are indicated. A potential region of midline is marked by the open arrowhead in P. (Q, R) 14 μM frozen cross sections through the diencephalon of 1 dpf (Q) WT or (R) MZoep embryos stained for otx5 expression. The midline of the brain (open arrowhead), and pineal precursors (closed arrowheads) are indicated. Dotted lines outline the neural tubes in panels O-R. Scale bars: 200 μm (A,B), 100 μm (C-E), 30 μm (F-J), 50 μm (K-R).
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Figure 3: Correlation between an expanded or divided pineal and an open neural tube. (A-E) Lateral views of live embryos at 1 dpf, anterior to the left. (A) While the head of the WT embryo is smooth and rounded, (B) the head of the sqt embryo is pointed (arrow). (C-E) Higher magnification of the anterior embryo reveals variability in the brain morphology of sqt mutants. In (C) WT embryos and (D) some sqt mutants, the border between the tectum and tegmentum (open arrowheads) appears as a smooth, straight line. (E) However, in some sqt mutants the border appears to be abnormally shaped or indistinct (open arrowhead), suggesting that the morphology of tectum or tegmentum is perturbed. (F-J) Embryos were fixed at 1 dpf, and processed for in situ hybridization with antisense probes for the pineal gene otx5 and the dorsal neural tube gene wnt1. In (F) WT and (G) sqt embryos with a single, round pineal anlage, the wnt1 expressing cells (open arrowheads) form a single domain along the dorsal neural tube. In contrast, sqt embryos with an (H) elongated or (I-J) divided pineal anlage have two parallel lines of wnt1 expressing cells. (K-P) Embryos were fixed at 1 dpf, processed for in situ hybridization with an antisense probe for epha4a, and then either (K-N) imaged in dorsal view, anterior to the left or (O, P) cut through epha4a-expressing rhombomere 5 to bisect the embryo into anterior and posterior halves. The locations of the otic vesicles (o), rhombomere 5 (arrows), and midline (open arrowhead) are indicated. A potential region of midline is marked by the open arrowhead in P. (Q, R) 14 μM frozen cross sections through the diencephalon of 1 dpf (Q) WT or (R) MZoep embryos stained for otx5 expression. The midline of the brain (open arrowhead), and pineal precursors (closed arrowheads) are indicated. Dotted lines outline the neural tubes in panels O-R. Scale bars: 200 μm (A,B), 100 μm (C-E), 30 μm (F-J), 50 μm (K-R).

Mentions: Since sqt mutants have not been previously shown to have a neural tube closure defect, we examined the neural tube by morphology in live embryos and through the expression of molecular markers. sqt mutants often had a "pinhead" appearance characteristic of other Nodal signaling mutants (such as oep) (Figure 3A,B), and a tectum and tectal ventricle that appeared disordered (Figure 3C–E).


Nodal signaling is required for closure of the anterior neural tube in zebrafish.

Aquilina-Beck A, Ilagan K, Liu Q, Liang JO - BMC Dev. Biol. (2007)

Correlation between an expanded or divided pineal and an open neural tube. (A-E) Lateral views of live embryos at 1 dpf, anterior to the left. (A) While the head of the WT embryo is smooth and rounded, (B) the head of the sqt embryo is pointed (arrow). (C-E) Higher magnification of the anterior embryo reveals variability in the brain morphology of sqt mutants. In (C) WT embryos and (D) some sqt mutants, the border between the tectum and tegmentum (open arrowheads) appears as a smooth, straight line. (E) However, in some sqt mutants the border appears to be abnormally shaped or indistinct (open arrowhead), suggesting that the morphology of tectum or tegmentum is perturbed. (F-J) Embryos were fixed at 1 dpf, and processed for in situ hybridization with antisense probes for the pineal gene otx5 and the dorsal neural tube gene wnt1. In (F) WT and (G) sqt embryos with a single, round pineal anlage, the wnt1 expressing cells (open arrowheads) form a single domain along the dorsal neural tube. In contrast, sqt embryos with an (H) elongated or (I-J) divided pineal anlage have two parallel lines of wnt1 expressing cells. (K-P) Embryos were fixed at 1 dpf, processed for in situ hybridization with an antisense probe for epha4a, and then either (K-N) imaged in dorsal view, anterior to the left or (O, P) cut through epha4a-expressing rhombomere 5 to bisect the embryo into anterior and posterior halves. The locations of the otic vesicles (o), rhombomere 5 (arrows), and midline (open arrowhead) are indicated. A potential region of midline is marked by the open arrowhead in P. (Q, R) 14 μM frozen cross sections through the diencephalon of 1 dpf (Q) WT or (R) MZoep embryos stained for otx5 expression. The midline of the brain (open arrowhead), and pineal precursors (closed arrowheads) are indicated. Dotted lines outline the neural tubes in panels O-R. Scale bars: 200 μm (A,B), 100 μm (C-E), 30 μm (F-J), 50 μm (K-R).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2214732&req=5

Figure 3: Correlation between an expanded or divided pineal and an open neural tube. (A-E) Lateral views of live embryos at 1 dpf, anterior to the left. (A) While the head of the WT embryo is smooth and rounded, (B) the head of the sqt embryo is pointed (arrow). (C-E) Higher magnification of the anterior embryo reveals variability in the brain morphology of sqt mutants. In (C) WT embryos and (D) some sqt mutants, the border between the tectum and tegmentum (open arrowheads) appears as a smooth, straight line. (E) However, in some sqt mutants the border appears to be abnormally shaped or indistinct (open arrowhead), suggesting that the morphology of tectum or tegmentum is perturbed. (F-J) Embryos were fixed at 1 dpf, and processed for in situ hybridization with antisense probes for the pineal gene otx5 and the dorsal neural tube gene wnt1. In (F) WT and (G) sqt embryos with a single, round pineal anlage, the wnt1 expressing cells (open arrowheads) form a single domain along the dorsal neural tube. In contrast, sqt embryos with an (H) elongated or (I-J) divided pineal anlage have two parallel lines of wnt1 expressing cells. (K-P) Embryos were fixed at 1 dpf, processed for in situ hybridization with an antisense probe for epha4a, and then either (K-N) imaged in dorsal view, anterior to the left or (O, P) cut through epha4a-expressing rhombomere 5 to bisect the embryo into anterior and posterior halves. The locations of the otic vesicles (o), rhombomere 5 (arrows), and midline (open arrowhead) are indicated. A potential region of midline is marked by the open arrowhead in P. (Q, R) 14 μM frozen cross sections through the diencephalon of 1 dpf (Q) WT or (R) MZoep embryos stained for otx5 expression. The midline of the brain (open arrowhead), and pineal precursors (closed arrowheads) are indicated. Dotted lines outline the neural tubes in panels O-R. Scale bars: 200 μm (A,B), 100 μm (C-E), 30 μm (F-J), 50 μm (K-R).
Mentions: Since sqt mutants have not been previously shown to have a neural tube closure defect, we examined the neural tube by morphology in live embryos and through the expression of molecular markers. sqt mutants often had a "pinhead" appearance characteristic of other Nodal signaling mutants (such as oep) (Figure 3A,B), and a tectum and tectal ventricle that appeared disordered (Figure 3C–E).

Bottom Line: N-cadherin expression and localization to the membrane are reduced in fish that lack Nodal signaling.Overexpression of an activated form of the TGFbeta Type I receptor Taram-A (Taram-A*) cell autonomously rescues mesendoderm formation in fish with a severe decrease in Nodal signaling.This work helps establish a role for Nodal signals in neurulation, and suggests that defects in Nodal signaling could underlie human neural tube defects such as exencephaly, a fatal condition characterized by an open neural tube in the anterior brain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, USA. axa161@case.edu

ABSTRACT

Background: Nodals are secreted signaling proteins with many roles in vertebrate development. Here, we identify a new role for Nodal signaling in regulating closure of the rostral neural tube of zebrafish.

Results: We find that the neural tube in the presumptive forebrain fails to close in zebrafish Nodal signaling mutants. For instance, the cells that will give rise to the pineal organ fail to move from the lateral edges of the neural plate to the midline of the diencephalon. The open neural tube in Nodal signaling mutants may be due in part to reduced function of N-cadherin, a cell adhesion molecule expressed in the neural tube and required for neural tube closure. N-cadherin expression and localization to the membrane are reduced in fish that lack Nodal signaling. Further, N-cadherin mutants and morphants have a pineal phenotype similar to that of mutants with deficiencies in the Nodal pathway. Overexpression of an activated form of the TGFbeta Type I receptor Taram-A (Taram-A*) cell autonomously rescues mesendoderm formation in fish with a severe decrease in Nodal signaling. We find that overexpression of Taram-A* also corrects their open neural tube defect. This suggests that, as in mammals, the mesoderm and endoderm have an important role in regulating closure of the anterior neural tube of zebrafish.

Conclusion: This work helps establish a role for Nodal signals in neurulation, and suggests that defects in Nodal signaling could underlie human neural tube defects such as exencephaly, a fatal condition characterized by an open neural tube in the anterior brain.

Show MeSH
Related in: MedlinePlus