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Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis.
Pan D
,
Rubin GM
.
???displayArticle.abstract??? Notch and the disintegrin metalloprotease encoded by the kuzbanian (kuz) gene are both required for a lateral inhibition process during Drosophila neurogenesis. We show that a mutant KUZ protein lacking protease activity acts as a dominant-negative form in Drosophila. Expression of such a dominant-negative KUZ protein can perturb lateral inhibition in Xenopus, leading to the overproduction of primary neurons. This suggests an evolutionarily conserved role for KUZ. The Notch family of receptors are known to be processed into smaller forms under normal physiological conditions. We provide genetic and biochemical evidence that Notch is an in vivo substrate for the KUZ protease, and that this cleavage may be part of the normal biosynthesis of functional Notch proteins.
Figure 3.
Injection of mRNA Encoding MKUZDN Leads to Supernumerary Primary Neurons in Xenopus Embryos and the Expression Pattern of a Xenopus kuz Gene
(A) and (B) show whole-mount Xenopus embryos at the neural plate stage hybridized with an N-tubulin probe. Normally, three stripes of primary neurons, medial (m), intermediate (i), and lateral (l), are present on each side of the neural plate (A). RNA encoding lacZ alone (A) or RNAs encoding both lacZ and MKUZDN (B) were injected into one cell of a 2–4 cell stage Xenopus embryo, and embryos were fixed at the neural plate stage. lacZ RNA served as a tracer to follow the distribution of the injected RNAs and was revealed by a lacZ substrate that gave a red color upon histochemical reaction. The lacZ negative side indicated the uninjected side and served as a control. Injection of RNA encoding MKUZDN resulted in extra N-tubulin positive cells as compared to the uninjected side (B) or to embryos injected with lacZ RNA alone (A). Extra neurons were observed in 72% (n = 156) of the embryos injected with MKUZDN. Note that these extra N-tubulin positive cells were confined to domains of primary neurogenesis and were not observed at ectopic positions.
(C), (D), (E), and (F) show expression patterns of a Xenopus kuz gene (Xkuz, partial sequence shown in Figure 1A) at different stages. (C) and (D) show the uniform expression of Xkuz in stage 13 embryos (dorsal view in [C] and lateral view in [D]). The ventral vegetal cells were not stained (D), most likely due to the low penetrance of probes into these cells. In older embryos, Xkuz continues to be widely expressed, with an elevated level in neural tissues (E and F).
