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    • Of the many thousands of

    2021-11-30

    Of the many thousands of mutations analyzed in tracheal terminal cells, less than a handful affect tube morphology specifically in the transition zone (Baer et al., 2007, Beitel and Krasnow, 2000, Förster et al., 2010, Ghabrial et al., 2011, Myat et al., 2005, Ruiz et al., 2012, Samakovlis et al., 1996). Among these we have previously described mutations in lotus, which causes a local transition zone tube discontinuity or gap, and mutations in GckIII and Ccm3, which cause a local transition zone tube dilation (Song et al., 2013). Intriguingly, mutations in Tao-1 cause both defects. The only other genetic condition reported to have this effect on terminal cell tubes is the combination of GckIII loss of function and knockdown of the septate junction protein, Varicose/PALS2 (Song et al., 2013). As in this case, loss of Tao-1 appears to both compromise GckIII activity and septate junction formation, given that Tao-1 mutant tracheal Gliotoxin synthesis exhibit transition zone dilation and mislocalization of septate junction proteins. These data suggest that Tao-1 performs at least two functions to control tracheal morphology: (1) it acts upstream of GckIII and Trc to prevent transition zone tube dilation; and (2) it is required to maintain the integrity of septate junctions. Trc appears to be the key substrate of GckIII, based on our biochemical data and that the trc loss-of-function phenotype closely phenocopies GckIII loss in trachea. Indeed, the trc tube dilation phenotype is, if anything, more severe than for Ccm3 or GckIII, with trc mutant terminal cells often exhibiting multiple large dilations in the transition zone. This would be consistent with residual Trc activity in GckIII mutant backgrounds, suggesting that additional Sterile-20 like kinases to GckIII may regulate Trc activity in terminal tracheal cells. If so, this would parallel regulation of D. melanogaster Wts and human LATS1 and LATS2 in the Hippo pathway, where multiple Sterile-20 kinases have been found to operate upstream of these NDR family kinases (Meng et al., 2015, Zheng et al., 2015, Li et al., 2014, Li et al., 2018). In D. melanogaster, Trc also regulates polarized cell growth that underpins hair and bristle development (Geng et al., 2000) and tiling and branching of PNS dendrites (Emoto et al., 2004). It will be interesting to determine whether Trc regulates the same or similar proteins to control these different biological processes or whether it regulates multiple proteins, akin to Wts, which regulates Yki in the context of organ growth and R8 cell fate choice, and the actin regulatory protein Enabled to control border cell migration in the D. melanogaster ovary (Lucas et al., 2013, Huang et al., 2005, Jukam et al., 2013). Furthermore, it will be important to determine whether Tao-1 and GckIII operate upstream of Trc in other biological settings. In addition to discovering the key substrate(s) of Trc in trachea, defining modes of upstream regulation of Tao-1 activity should provide insights into how this Hippo-like signaling module controls tube development. One candidate upstream regulator is Schip1, which has been linked to Tao-1 and the Hippo pathway in the context of organ size control (Chung et al., 2016), although the mechanism by which it functions is unclear. Previous findings by our group and others in both insects and vertebrates established the human orthologs of GckIII (MST3, MST4, and STK25) as potential disease genes in cerebral cavernous malformation, a familial vascular syndrome characterized by dilated leaky blood vessels (Song et al., 2013, Draheim et al., 2014). hGCKIII kinases bind to the non-catalytic protein CCM3, which is thought to serve as a scaffold for them. Theoretically, CCM3 could promote the association of GCKIII kinases with TAO kinases and/or NDR family kinases to facilitate their ability to phosphorylate one another and become active. This requires further examination, but our findings raise the possibility that the Tao-regulated Hippo-like signaling module identified here is required for proper blood vessel formation in humans and that aberrant activity of this module could contribute to cerebral cavernous malformation syndrome. If so, then our study could provide potential therapeutic targets for treatment of this disease.