The role of LRP2 in sonic hedgehog dependent adult neurogenesis

Abstract

LRP2 is an endocytic receptor of the LDL receptor gene family expressed on the apical surface of absorptive epithelia in the embryonic and the adult mammalian organisms. Binding a functionally diverse array of ligands, including morphogens, this receptor plays a crucial role not only in endocytosis but also in regulation of signal transduction in various cell types during embryonic development and in adulthood. LRP2 is best known for its ability to mediate cellular uptake of the morphogens sonic hedgehog (SHH) and bone morphogenetic protein (BMP) 4, an activity required to establish SHH and BMP signaling centers in the embryonic neural tube. Loss of receptor expression in gene targeted mice or in patients with inheritable LRP2 gene defect (Donnai Barrow syndrome) results in disturbances in neural tube neurogenesis and in malformation of the embryonic forebrain.

Intriguingly, expression of LRP2 persists in ependyma cells of adult mammalian brain. Ependymal cells are part of the neurogenic niche of the subventricular zone (SVZ), one of two regions of the adult mammalian brain capable of sustained neurogenesis. A possible role for LRP2 in adult neurogenesis was supported by earlier work documenting a decreased proliferative capacity in the SVZ of adult receptor mutant mice. Still, the molecular details of receptor function in adult neurogenesis remained obscure. I addressed this important question by performing detailed investigations of the adult neurogenesis and relevant ependymal cell functions in wild-type and LRP2-deficient mouse models as well as in brain explants and primary ependymal cell lines derived thereof.

In my studies, I uncovered defects in SHH signaling in LRP2-deficient mice in the rostral but not the caudal regions of the SVZ. A region-specific impact of receptor deficiency in the SVZ was also observed for other morphogen pathways, including BMP and WNT, as well as for mTOR activtity in this niche. The region-specific alterations in morphogen signaling in the SVZ coincided with a loss of the neural stem cell population and with impaired neurogenesis in the rostral but not the caudal region of the LRP2-deficient SVZ. Finally, the regional specificity in LRP2 action in the adult brain was substantiated by documenting aberrant accumulation of SHH in the caudal SVZ. Jointly, the above findings argued for a global effect of LRP2 activity on spatial control of adult neurogenesis in the mouse brain. This hypothesis received experimental support by documenting a defect in coordination of motile cilia beating in ependymal cells of LRP2 deficient mice. Because coordination of cilia beating is essential to control the flow of the cerebrospinal fluid (CSF) in a caudal to rostral direction, these findings suggested disturbed CSF flow and, hence, faulty distribution of morphogens to underlie the region-specific impact of receptor deficiency on morphogen signaling and adult neurogenesis in the SVZ. The molecular mechanism of LRP2 action in motile cilia function still remains to be fully established. However, my observations of the localization of LRP2 to the endocytically active ciliary pocket and of an altered distribution of endocytic markers in motile cilia from receptor mutant cells supports a role for LRP2 in controlling endocytic processes that safeguard coordinated cilia beating and thereby proper morphogen distribution in the neurogenic niche of the SVZ.