Building a symmetrical forebrain and face
The two hemispheres of the human forebrain and the features of the face arise in the early embryo from a structure called the neural tube. The foremost part of this tissue, called the rostral diencephalon (RD), has a stripe of cells that run through its mid-line and organize the development of symmetrical forebrain structures on either side. To do so, the cells have to receive and properly interpret a molecular signal from neighboring tissue. If they fail to do so, the result is holoprosencephaly, the most common defect of the human forebrain. Its most pronounced form, cyclopia, produces an embryo with a fused forebrain, a single eye, and other facial abnormalities. Severe holoprosencephaly often leads to miscarriages or early infant mortality. Annabel Christ in Thomas Willnow's lab and Delbrück fellow Annette Hammes have now worked out crucial details of the molecular dialogue that triggers forebrain development. Their work, published in the Feb. 14 issue of Developmental Cell, helps explain why the process often fails.
A molecular signal called _SHH_ is crucial for proper forebrain development. Here the scientists showed that an additional protein called _LRP2_ is necessary for SHH to dock onto the receptor _Patched1_. When the three molecules form a complex, they are drawn into the cell and pass along the developmental signal. This also permits SHH to be recycled to the cell surface, where it probably increases the strength of the signal.
Over a decade ago, scientists identified the signal that activates the mid-line cells in the neural tube as a protein called sonic hedgehog (SHH). Tissue underneath the RD releases SHH, which binds to a receptor called patched1 on the surface of cells of the mid-line. This normally happens during the fifth and sixth weeks of a human pregnancy. Defects in either the signal or its receptor lead to holoprosencephaly.
In 2005, Thomas' lab showed that problems with yet another protein, called LRP2, have a similar effect on mice, but the reasons were unclear. Subsequently, LRP2 was found to have an equally important role in humans. Defects in this gene cause a condition called Donnai–Barrow syndrome, which affects the face and many other parts of the body and can also cause holoprosencephaly.
Two years later the scientists discovered that LRP2 appears on the surface of cells in early brain tissue. The current study now defines its role: LRP2 is another binding partner of SHH that must be present with patched1 for cells to interpret the signal. Alongside this binding function, the molecule helps to transport SHH into the cell and to process it.
Annabel, Annette and their colleagues demonstrated with experiments in mice that LRP2 helps to cluster SHH molecules on the surface of target cells as the signal arrives. If the mid-line cells don't produce LRP2, SHH fails to dock onto patched1.
Earlier work from many labs has shown that proteins related to LRP2 – a family of molecules called the low-density lipoprotein receptors – are frequently involved in drawing signaling molecules into the cell. This puts important signals into contact with internal molecules that receive them. It may also lead to the "recycling" of the receptor or molecules bound to it, allowing them to move back to the cell surface.
The new experiments show that LRP2 is necessary to draw SHH and patched1 into the cell. This not only establishes contact with further cellular molecules that interpret the signal, it delivers SHH to a recycling "pathway". Presumably this returns SHH to the cell surface as a way of strengthening the signal. Earlier studies have suggested that such amplification, in a specific time window during development, is necessary for proper forebrain development.
- Russ Hodge
Highlight Reference:
Christ A, Christa A, Kur E, Lioubinski O, Bachmann S, Willnow TE, Hammes A. LRP2 is an auxiliary SHH receptor required to condition the forebrain ventral midline for inductive signals. Dev Cell. 2012 Feb 14;22(2):268-78.
