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Review
. 2010;50(1):309-23.
doi: 10.1016/j.advenzreg.2009.10.018. Epub 2009 Nov 13.

Zebrafish inositol polyphosphate kinases: new effectors of cilia and developmental signaling

Bhaskarjyoti Sarmah  1 , Susan R Wente
Affiliations
Review

Zebrafish inositol polyphosphate kinases: new effectors of cilia and developmental signaling

Bhaskarjyoti Sarmah et al. Adv Enzyme Regul. 2010.
No abstract available

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Figures

Fig. 1
Fig. 1. The pathways for synthesis of soluble inositol polyphosates (IPs) in yeast and vertebrates
IP production is initiated with the synthesis of IP3 through PLC catalyzed hydrolysis of PI(4,5)P2. IP3 undergoes sequential modifications by specific kinases and phosphatases to produce more highly phosphorylated IP molecules, including inositol tetrakisphosphate (IP4) isomers, inositol 1,3,4,5,6-pentakisphosphate (IP5), inositol hexakisphosphate (IP6), and inositol pyrophosphate isomers (e.g., PP-IP4, IP7, and IP8). The pathways intervening between IP3 and IP5 are diversified across species. In yeast, IP3 is sequentially phosphorylated to IP5 by the dual-specificity kinase Ipk2, whereas, three specific kinases and a phosphatase are involved in the production of IP5 from IP3 in vertebrates (see text for details). Black arrows indicate PLC-driven hydrolysis and IP kinase-driven phosphorylation, and grey arrows indicate dephosphorylation reactions.
Fig. 2
Fig. 2. The production of IP6 is required for left-right (LR) axis specification and normal placement of body organs
(A) Normal asymmetry of the heart tube placement is randomized in Ipk1 depleted zebrafish embryos. Live fluorescent and DIC overlay images at 28 hours post fertilization (hpf) of uninjected embryos (left) and embryos injected with the ipk1 morpholino (ipk1MO) (right) that were expressing Tg(cmlc2-EGFP) (Huang et al., 2003) for EGFP throughout the myocardium. Nearly 50% of the ipk1MO injected embryos display reversed (right-sided) heart tube placement in contrast to its consistent left-sided placement in the uninjected embryos. (B) Model displaying connections between Ipk1/IP6 production, cilia, and left-biased Ca2+ signaling during LR-axis specification. LR-axis specification emerges from three positional cues: anterior (a) - posterior (p) axis, dorsal-ventral axis, and chirality of the nodal (KV) ciliary beating. Once the LR-axis is specified, the LR information is relayed through the action of a set of long-range signaling molecules (e.g., nodal, lefty1, and lefty2) and induction of the homeobox transcription factor gene pitx2 culminating in situs-specific morphogenesis. The left-biased Ca2+ signaling induced by ciliary beating acts as the connector between cilia and LR signaling molecules. Lefty1 functions as a midline barrier restricting LR signals to the left. Shown here are KV cilia (in red) detected by anti-acetylated tubulin immunohistochemistry superimposed on a live fluorescent image displaying left-biased Ca2+ flux (in green as revealed by flash-pericam Ca2+ indicator protein). Our studies reveal that Ipk1 activity is essential for KV ciliary beating. Thus, loss of Ipk1 might directly impact the LR cascade downstream of cilia. On the other hand, ipk1 is expressed in cells enveloping KV and it might mediate expansion of asymmetric Ca2+ flux, initiated by motile KV cilia, across cell fields. This could drive asymmetric expression of signaling molecules. Bright-field low magnification image (ventral view) of a 12 hpf embryo showing the KV is presented on the bottom-right.
Fig. 3
Fig. 3. Ipk1 depleted zebrafish embryos display curved body axis and dilation of pronephric tubules
Disruption of ipk1 function by ipk1MO injection results in ventrally curved body axis at 72 hpf (B) compared to uninjected embryos (A). ipk1MO embryos also develop pronephric cyst, hydrocephalus, and pericardial edema at 5 dpf (not shown). Histological cross sections of an uninjected embryo (C) and an ipk1MO embryo at 72 hpf (D) show the midline fused glomerulus, pronephric tubules (red arrowhead), and paired pronephric ducts (yellow arrowhead) on either side. ipk1MO embryos show dilation of pronephric tubules (red arrowhead) and pronephric ducts (yellow arrowhead).
Fig. 4
Fig. 4. The IP kinase IP6k2 is required the normal development of craniofacial skeleton
(A,B) Live images of uninjected (A) and ip6k2MO injected zebrafish embryos at 5 days post fertilization (dpf). (C,D) Images of alcian blue stained head skeletons of uninjected (C) and ip6k2MO injected (D) embryos at 5 dpf. The flat-mount (ventral) images display normal pharyngeal skeleton and parts of the neuroocranium of the uninjected embryos (C). In the IP6k2 depleted embryos, most of the cartilage elements of the pharyngeal skeleton are not formed and have a shortened neuroocranium (D). e, eye; m, Meckel’s cartilage; pq, palatoquadrate; ch, ceratohyal; cb 3–7, ceratobranchials arches 3 to 7; eth, ethmoid plate; nc, notochord.
Fig. 5
Fig. 5. IPs might act as effectors of a versatile cilia-based signaling network
Presented here is a model showing that IPs, after synthesized in response to an activated GPCR, transduce extracellular signals to cilia and/or cell anterior. In primary cilia, PP-IP4 plays an as “yet undefined” role during hedgehog signaling response, controlling critical developmental and morphogenetic events (e.g., craniofacial and somite developments). On the other hand, IP6 acts as an effector of ciliary motility and/or IFT. The IP6 role(s) in motile cilia are essentially required for key developmental processes (e.g., LR-axis specification) as well as maintenance and functions of organs (e.g., kidney).
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