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Ectopic bone morphogenetic proteins 5 and 4 in the chicken forebrain lead to cyclopia and holoprosencephaly
J A Golden1, A Bracilovic, K A McFadden
1Department of Pathology, Children's Hospital of Philadelphia, and the University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. goldenj@mail.med.upenn.edu
Insights
Bone morphogenetic proteins (BMPs) are crucial for vertebrate forebrain development. BMP signaling disruption leads to holoprosencephaly and cyclopia, demonstrating BMPs
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Dorsal-ventral patterning is essential for central nervous system development.
- Bone morphogenetic proteins (BMPs) and Sonic hedgehog protein regulate caudal neural tube patterning.
- The role of BMPs in rostral brain development is less understood.
Purpose of the Study:
- To investigate the role of BMPs in dorsal-ventral patterning of the vertebrate forebrain.
- To test the hypothesis that BMPs contribute to dorsal specification in the developing brain.
Main Methods:
- Implantation of recombinant BMP4 or BMP5 soaked beads into the chicken forebrain neural tube.
- In situ hybridization to analyze gene expression patterns in dorsal and ventral forebrain markers.
- Assessment of forebrain malformations including holoprosencephaly and cyclopia.
Main Results:
- BMP signaling disruption resulted in holoprosencephaly, cyclopia, and loss of ventral midline structures.
- Ventral forebrain markers were downregulated, while dorsal markers remained expressed.
- Excessive cell death in the basal telencephalon, rather than altered cell fates, caused the observed malformations.
Conclusions:
- BMP signaling plays a critical role in the dorsal-ventral patterning of the developing vertebrate brain.
- Disturbances in BMP signaling lead to specific forebrain malformations.
- These findings highlight the importance of precise BMP signaling for normal forebrain development.
Abstract:
Proper dorsal-ventral patterning in the developing central nervous system requires signals from both the dorsal and ventral portions of the neural tube. Data from multiple studies have demonstrated that bone morphogenetic proteins (BMPs) and Sonic hedgehog protein are secreted factors that regulate dorsal and ventral specification, respectively, within the caudal neural tube. In the developing rostral central nervous system Sonic hedgehog protein also participates in ventral regionalization; however, the roles of BMPs in the developing brain are less clear. We hypothesized that BMPs also play a role in dorsal specification of the vertebrate forebrain. To test our hypothesis we implanted beads soaked in recombinant BMP5 or BMP4 into the neural tube of the chicken forebrain. Experimental embryos showed a loss of the basal telencephalon that resulted in holoprosencephaly (a single cerebral hemisphere), cyclopia (a single midline eye), and loss of ventral midline structures. In situ hybridization using a panel of probes to genes expressed in the dorsal and ventral forebrain revealed the loss of ventral markers with the maintenance of dorsal markers. Furthermore, we found that the loss of the basal telencephalon was the result of excessive cell death and not a change in cell fates. These data provide evidence that BMP signaling participates in dorsal-ventral patterning of the developing brain in vivo, and disturbances in dorsal-ventral signaling result in specific malformations of the forebrain.