The survival of multi-cellular organisms depends on communication networks that coordinate the growth, differentiation, death, and metabolism of cells in diverse tissues and organs. At the cellular level, intracellular signal transduction pathways sense changes outside the cell and generate appropriate cellular responses. One such widely utilized mechanism is cellular inositol signaling. The classic paradigm of inositol signaling involves receptor-mediated stimulation of soluble inositol polyphosphate (IP) production. The lipid anchored phosphatidylinositol 4,5-bisphosphate (PIP2) is the effective starting point with regulated hydrolysis by phospholipase C (PLC) producing diacylglycerol (DAG) and soluble inositol 1,4,5-triphosphate (IP3) (1). IP3 regulates the release of intracellular calcium, whereas DAG activates protein kinase C, both of which in turn initiate diverse cellular events (2). In addition, IP3 itself is also the linchpin upon which specific inositol kinases and phosphates rely for generation of all other cellular soluble IPs. For example, IP3 is sequentially phosphorylated to produce inositol tetrakisphosphate (IP4) isomers, inositol 1,3,4,5,6-pentakisphosphate (IP5), inositol hexakisphosphate (IP6), and inositol pyrophosphates (e.g., IP7) (3-6). Each isomer is potentially generated by coordinated actions of specific kinases and phosphatases.
Perturbation of inositol signaling may result in pathophysiological states that include neurological disorders and cancer of the brain, prostate, and skin (7). However, the cellular functions and roles in development and disease for many of the IPs are unknown. We initiated an effort to understand the roles of different IPs in vertebrate development using the zebrafish model system. Recently, we reported that the enzyme inositol 1,3,4,5,6-pentakisphosphate (IP5) 2-kinase (Ipk1), responsible for conversion of IP5 to IP6 plays a critical role in the establishment of left-right (LR) asymmetry, mediating a left-biased calcium flux in cells enveloping the Kupffer's vesicle (KV), a transient ciliated structure essential for the LR asymmetry determination (8). Strikingly, our follow-up studies revealed that Ipk1 activity is also critical for ciliary beating and length maintenance. Altogether, these findings for the first time link the IP pathway to diverse aspects of vertebrate development and physiology and demonstrate how intracellular signal transduction pathways influence critical developmental decisions. We have also started testing other components of the IP pathway that act upstream or downstream of Ipk1.
1. R.F. Irvine. Nat. Rev. Mol. Cell Biol. 4, 586 (2003).
2. M.J. Berridge, P. Lipp and M.D. Bootman. Nat. Rev. Mol. Cell Biol. 1, 11 (2000).
3. R.F. Irvine and M.J. Schell. Nat. Rev. Mol. Cell Biol. 2, 327 (2001).
4. A.R. Odom, A. Stahlberg, S.R. Wente and J.D. York. Science 287, 2026 (2000).
5. S.B. Shears. Biochem. J. 377, 265 (2004).
6. J.D. York, A.R. Odom, R. Murphy, E.B. Ives and S.R. Wente. Science 285, 96 (1999).
7. C. Pendaries, H. Tronchere, M. Plantavid and B. Payrastre. FEBS Lett. 546, 25 (2003).
8. B. Sarmah, A.J. Latimer, B. Appel and S. R. Wente. Dev. Cell 9, 133 (2005).
Vanderbilt University is committed to principles of
equal opportunity and affirmative action.