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The MLK family of mitogen activated protein kinase kinase kinases (MAPKKK) has been shown to activate Jun N-terminal kinase/stress-activated protein kinase 1 (JNK/SAPK1). However, little is known of the in vivo functions of the MLKs. We have identified a Xenopus laevis MLK that shows highest homology with mammalian MLK2 (62%) and, like MLK2, interacts preferentially with the Rho-family GTPase Rac. xMLK2 was expressed zygotically from late gastrula/early neurula. Surprisingly, this expression was restricted to the cement gland, the brain, and the pronephros. In the differentiating cement gland, xMLK2 expression correlated with cell elongation and the onset of a previously unobserved apoptotic phase, while in the pronephros, expression corresponded with the differentiation and opening of the nephric tubules. Overexpression of xMLK2 in COS7 cells led to a SEK1/MKK4 (MAPKK)-dependent hyperactivation of JNK in response to UV irradiation. xMLK2 was shown to be required for normal cement gland development and pronephric tubule formation using antisense inactivation and a dominant negative xMLK2. The data suggest a novel role for the MLKs as tissue-restricted mediators of signal transduction. They also suggest that tissue-specific responses to common extracellular signals may in part result from the programmed expression of MAPKKKs with differing specificities.
Fig. 3. Early zygotic expression of xMLK2 was detected by whole-mount in situ hybridization in the cement gland, pronephros, and brain. (A) xMLK2 mRNA was first detected at stage 22 in the cement gland (CG). (B) By stage 24, xMLK2 was noted most strongly in the peripheral of the cement gland. (C) Stage 25 embryos showed two concentric rings of expression around the cement gland. The eye anlage is outlined in gray. (D) In situ hybridization with the early cement gland marker, xCG (Sive et al., 1989), on stage 25 embryo showed staining around the cement gland. (E) Stage 30 embryo showing expression in the cement gland and in the pronephric anlage (PA). (F and G) Stage 32 and 36 embryos showing xMLK2 expression in the developing pronephros (P) and weakly in the pronephric duct (PD). (H) Stage 37, xMLK2 was expressed in the functional pronephros (P) and much more weakly in the pronephric duct. Panels are lateral views with anterior to left.
Fig. 4. The onset of xMLK2 expression corresponds with epithelialisation of the proximal pronephric tubules. (A) Whole-mount in situ views compared with a schematic representation of the developing pronephros adapted from (Vize et al., 1995). All panels are lateral views with anterior to the left. Expression closely followed the differentiation of each proximal tubule branch, starting with the most anterior one, see stage 28–29, and moving towards the most posterior one by stage 35–36. At stages 36 and 37–38, expression was restricted to the proximal tubules and probably to the connecting common tubule. In the schematic, dark shading represents the proximal and common tubule tissue, where xMLK2 is expressed, and light shading the pronephric duct. Dotted line on stage 37–38 pronephros traces the weak xMLK2 staining in the pronephric duct. (B) Transverse section through the pronephros of a stage 37 X. laevis embryo stained for xMLK2 by whole-mount in situ hybridization. (C) Schematic representation of a transverse embryo section at the level of the pronephros at stage 36 showing the localisation of the pronephric tubules, duct, glomus and coelom, adapted from Vize et al., 1995. (D and E) xMLK2 was expressed in pronephric tubule epithelium. In these sections, tubules were oriented in an anterioposterior (D) or dorsoventral (E) fashion. (F) enlargement of an xMLK2-stained section showing both anterioposterior and dorsoventral oriented tubules. PT, pronephric tubules; E, epiderm.
muc2 (mucin 2, oligomeric mucus/gel-forming) gene expression in Xenopus laevis embryos, NF stage 25, as assayed by in situ hybridization, lateral view, anteriorleft, dorsal up.
