Science / January 06, 2005

LRP2/megalin is required for patterning of the ventral telencephalon

Holoprosencephaly (HPE) is the most common developmental forebrain anomaly in humans and is caused by the failure of the prosencephalon (the embryonic forebrain) to sufficiently divide into the double lobes of the cerebral hemispheres. The result is a single-lobed brain structure and severe skull and facial defects. About 1 in 250 pregnancies miscarries as a result of severe HPE. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip, such as median cleft lip and palate.

It is known that megalin, a low-density lipoprotein receptor-related protein (LRP2), is essential to normal forebrain development. Megalin deficient (-/-) mice develop malformations mirroring those seen in HPE. Now, Thomas Willnow and colleagues have zeroed in on this critical role (Development 132 (2) January 15, 2005: pp. 405-414).

Comparing the ubiquitous with the neuroepithelial-specific inactivation of the megalin gene in the mouse, the researchers showed that megalin is essential within the neuroepithelium to prevent HPE-like defects and for the correct establishment of specific neuronal cell fates within the forebrain. Willnow and colleagues provided further insight into the mechanism of megalin function by demonstrating that it affects two important signaling pathways that set up dorsal-ventral pattern within the neural tube- namely, the sonic hedgehog (SHH) and the bone morphogenetic protein 4 (BMP4) pathways. These findings identify megalin as a key regulator of the dorsal-ventral patterning system possibly by acting as clearance receptors for morphogens such as BMP4.

Contact:

Pamela Cohen
p.cohen@mdc-berlin.de
+49 30 9406 2121

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