Development of Retinal and Brain Blood Barriers Controlled by Norrin/Frizzled4 Signaling

The activity of the Norrin/Frizzled4 protein pair in the embryo controls development of the retinal and brain blood barriers, and the timing of this activity is critically linked to precise blood vessel formation.

Norrin/Frizzled4 (Fz4) signaling activates the canonical Wnt pathway that controls conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. To determine how this signaling activity would affect the later development of the animal, investigators at Johns Hopkins University (Baltimore, MD, USA;) genetically engineered lines of mice to lack the gene for Norrin, Fz4, or for both genes. The technique that was used gave the investigators temporal and tissue-specific control of Norrin/Fz4 signaling. Other mice were engineered to express Norrin activity at an earlier stage of development than was normal.

Results published in the December 7, 2012, issue of the journal Cell revealed that early initiation of Norrin production led to premature retinal vascular invasion. Delayed Norrin production led to characteristic defects in intraretinal vascular architecture.

In the adult retina and cerebellum, gain or loss of Norrin/Fz4 signaling resulted in a cell-autonomous gain or loss, respectively, of blood retina barrier and blood-brain barrier function, indicating an ongoing requirement for Frizzled signaling in barrier maintenance and substantial plasticity in mature central nervous system vascular structure.

Although crucial to protecting the central nervous system, the blood-brain barrier also prevents drugs in the bloodstream from penetrating the brain to treat diseases. "Our research shows that blood vessel cells lacking Frizzled-4 are leaky," said senior author Dr. Jeremy Nathans, professor of molecular biology and genetics at Johns Hopkins University. "With this information in hand, we hope that someday it may be possible to temporarily loosen the blood-brain barrier, allowing life-saving drugs to pass through."

Related Links:
Johns Hopkins University