Frizzledsphysiology And Possible Therapy 541 Frizzleds in Physiology

It is well established that FZDs have a prominent role during embryonic development and in cancer. These topics exceed the scope of this chapter, and the reader is therefore referred to a series of excellent overviews [89-93] . One future challenge for the analysis of FZD function in physiology and patho-physiology will be to distinguish (dys-)function of FZDs in the adult organism from WNT/FZD-dependent defects arising during embryonic development. Understanding of basal signaling paradigms, FZD pharmacology, and their involvement in adult tissue homeostasis and pathophysiology will provide novel opportunities to treat diseases of the immune, nervous, and cardiovascular systems. Not unexpectedly, WNT/FZD signaling is important for the maintenance, proliferation, and differentiation of adult stem cells. Apart from that, very little is known as yet about the role of WNT/FZD signaling for physiology in the adult organism.

Novel physiological tasks for the WNT/FZD system are emerging from recent studies. Important roles in the brain include retrograde WNT signaling for axon guidance and synaptogenesis [94], the regulation of neurotransmitter release [95-97], and the modulation of N-methyl-D-aspartate (NMDA)-induced long-term potentiation [98]. Furthermore, as expected from their prominent role during organ development, signaling via WNT/FZD also serves some key but as yet poorly defined function in response to trauma, for tissue regeneration and tissue repair, such that WNT/FZD signaling might emerge as a hallmark of tissue trauma.

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