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J Biol Chem
2012 Mar 02;28710:6974-8. doi: 10.1074/jbc.C111.323618.
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The signaling protein CD38 is essential for early embryonic development.
Churamani D
,
Geach TJ
,
Ramakrishnan L
,
Prideaux N
,
Patel S
,
Dale L
.
???displayArticle.abstract??? CD38 is a multifunctional protein possessing ADP-ribosyl cyclase activity responsible for both the synthesis and the degradation of several Ca(2+)-mobilizing second messengers. Although a variety of functions have been ascribed to CD38, such as immune responses, insulin secretion, and social behavior in adults, nothing is known of its role during embryonic development when Ca(2+) signals feature prominently. Here, we report the identification and functional expression of CD38 from Xenopus laevis, a key model organism for the study of vertebrate development. We show that CD38 expression and endogenous ADP-ribosyl cyclase activity are developmentally regulated during cellular differentiation. Chemical or molecular inhibition of CD38 abolished ADP-ribosyl cyclase activity and disrupted elongation of the anterior-posterior axis and differentiation of skeletal muscle, culminating in embryonic death. Our data uncover a previously unknown role for CD38 as an essential regulator of embryonic development.
FIGURE 2. Xenopus CD38 is developmentally regulated. A, RT-PCR analysis of Xenopus CD38 expression in staged Xenopus embryos. Ubiquitously expressed ornithine decarboxylase (ODC) and RNA (stage 33) without reverse transcriptase (−RT) were used as controls. Embryos were collected as blastulae (stage 8), gastrulae (stages 12 and 13), neurulae (stages 15 and 22), and tailbud stages (stages 25 and 33). B, whole mount in situ hybridization for CD38 expression (purple stain) in Xenopus embryos (anterior to left and posterior to right). B, dorsal view of a stage 16 embryo. C, cross section of a stage 16 embryo with neural plate (np), notochord (n), somites (s), and endoderm (e) indicated. D, lateral view of a stage 23 embryo. E, lateral view of a stage 30 embryo. F, time courses for endogenous ADP-ribosyl cyclase activities in Xenopus homogenates from stage 11 and stage 36 embryos, showing production of ADPR from NAD, cGDPR from NGD, and NAADP from NADP and nicotinic acid (NA). Nic, nicotinamide. G, stage-dependent NADase activity (ADPR production from NAD) in Xenopus embryo homogenates. H, region-specific NADase activity in fragments from stage 36 embryos. H, head; D, dorsal abdomen; V, ventral abdomen; T, tail. Error bars represent mean S.E.
FIGURE 3. Inhibition of CD38 disrupts Xenopus development. A and B, time courses for endogenous NADase activity (ADPR production from NAD) in Xenopus homogenates from stage 30 embryos. A, homogenates incubated with increasing concentrations (0, 1, 3, and 30 mM) of Nic. B, homogenates from embryos injected with either 20 ng of control morpholino (CMO) or 100 ng of CD38-AMO. C, lateral views of stage 30 embryos (head on the left). C, untreated control embryo. D, embryo incubated in 30 mM Nic from stage 13 to stage 30. E, embryo injected with 20 ng of CMO. F, embryos injected with 20 ng of CD38-AMO. G, length of anterior-posterior (head-tail) axis of Xenopus embryos with inhibited CD38 activity. Cont, control; Nic, 30 mM nicotinamide; CMO, 20 ng; AMO, 20 ng of CD38-AMO; RNA, 1.5 ng of CD38 mRNA. Error bars represent mean S.E. of 364 embryos (***, p < 0.005). H, lateral views of stage 30 embryos stained for skeletal muscle with 12/101 monoclonal antibody (head on the left). H, untreated control embryo. I, embryos incubated in 30 mM Nic from stage 13 to stage 30. J, embryo injected with 20 ng of CMO. K, embryos injected with 20 ng of CD38-AMO.
cd38 (CD38 molecule) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 23, lateral view, anteriorleft, dorsal up.
cd38 (CD38 molecule) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 30, lateral view, anteriorleft, dorsal up.
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