Proteolytic cleavage of Slit by the Tolkin protease converts an axon repulsion cue to an axon growth cue <i>in vivo</i>

Kellermeyer, Riley; Heydman, Leah M.; Gillis, Taylor; Mastick, Grant S.; Song, Minmin; Kidd, Thomas

doi:10.1242/dev.196055

Cited by 9 publications

(6 citation statements)

References 74 publications

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“…Our observations that tok overexpression inhibits proliferation and impairs wing growth suggest that tok is unlikely to do so through activation of Dpp. Consistent with tok having additional cleavage targets, recent studies have revealed functions in proteolytic cleavage of the axon-guidance protein Slit ( Kellermeyer et al, 2020 ). Given the significant growth inhibitory functions of tok in the wing, unbiased approaches to identify pro-proliferative targets will be of great interest.…”

Section: Discussionmentioning

confidence: 95%

Psi promotes Drosophila wing growth via direct transcriptional activation of cell cycle targets and repression of growth inhibitors

et al. 2023

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The first characterised FUSE Binding Protein family member, FUBP1, binds single-stranded DNA to activate MYC transcription. Psi, the sole FUBP protein in Drosophila, binds RNA to regulate P-element and mRNA splicing. Our previous work revealed pro-growth functions for Psi, which depend, in part, on transcriptional activation of Myc. Genome-wide functions for FUBP family proteins in transcriptional control remain obscure. Here, through the first genome-wide binding and expression profiles obtained for a FUBP family protein, we demonstrate that, in addition to being required to activate Myc to promote cell growth, Psi also directly binds and activates stg to couple growth and cell division. Thus, Psi knockdown results in reduced cell division in the wing imaginal disc. In addition to activating these pro-proliferative targets, Psi directly represses transcription of the growth inhibitor tolkin (tok, a metallopeptidase implicated in TGFβ signalling). We further demonstrate tok overexpression inhibits proliferation, while tok loss of function increases mitosis alone and suppresses impaired cell division caused by Psi knockdown. Thus, Psi orchestrates growth through concurrent transcriptional activation of the pro-proliferative genes Myc and stg, in combination with repression of the growth inhibitor tok.

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Section: Discussionmentioning

confidence: 95%

Psi promotes Drosophila wing growth via direct transcriptional activation of cell cycle targets and repression of growth inhibitors

et al. 2023

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“…As another example, Egr-2 might also control the influence of extracellular matrix or secreted cues that influence remodeling, since numerous proteases are dysregulated in egr-2(RNAi) regenerates (Table S1). Intriguingly, the Drosophila metalloprotease Tolkin cleaves Slit and converts it from a repulsive to a growth-promoting ligand 78 . A similar reduction in post-translational Slit-1 processing in egr-2(RNAi) regenerates could increase, rather than decrease, Slit-1-mediated repulsion, inhibiting midline fusion.…”

Section: Discussionmentioning

confidence: 99%

Egr-2 coordinates intestinal remodeling by promoting midline patterning and pharynx regeneration in planarians

Morkotinis

Forsthoefel

2023

Preprint

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Regeneration requires remodeling of pre-existing structures and their integration with new cells and tissue. Identification of wound-induced regulators of these processes is central to regenerative biology. In planarian flatworms, the intestine remodels after amputation to re-establish normal morphology and integrate with the regenerating pharynx, the centrally located feeding organ. How these events are initiated and coordinated is currently unclear. In a candidate screen for wound-induced regulators of intestinal regeneration, we found that Early growth response protein 2 (Egr-2) was required for collective migration and fusion of intestinal branches at the anterior midline. Even though inhibition ofegr-2by RNA interference increased dorsoventral (DV) muscle fibers at the midline between intestinal branches, bulk RNA sequencing of regenerating tissue revealed negligible dysregulation of DV-, body wall-, or intestinal-muscle-associated transcripts. Instead, the midline polarity cueslit-1and subsets of pharynx-associated transcripts were dysregulated. Consistently, bothegr-2andslit-1RNAi delayed early pharynx regeneration, consistent with reducedslit-1expression inegr-2(RNAi)regenerates in the region of pharynx specification. Furthermore, inhibition of pharynx regeneration regulatorsfoxF-1andfoxAdelayed integration with the intestine and disrupted formation of the intestine's midline anterior branch. Our findings suggest that the regenerating pharynx plays an inductive role in initiation of intestinal remodeling, and that Egr-2 orchestrates the temporal and spatial reprogramming of gene expression necessary for this critical step.

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“…Structurally, it consists of a putative signal peptide, four leucine-rich repeats (LRRs), 7 ( Drosophila SLIT) to 9 (vertebrate SLIT) epidermal growth factor (EGF) repeats, a laminin G domain, and a cysteine-rich domain ( Rothberg et al, 1990 ; Rothberg and Artavanis-Tsakonas, 1992 ) ( Figure 1 ). Most SLIT proteins can be fragmented by an unknown protease between the fifth and sixth EGF repeats, with a conserved proteolytic site ( Brose et al, 1999 ; Wang et al, 1999 ; Patel et al, 2001 ; Kellermeyer et al, 2020 ).…”

Section: Structure and Characteristics Of Slit Proteinsmentioning

confidence: 99%

Role of the SLIT-ROBO signaling pathway in renal pathophysiology and various renal diseases

Shu

Sun

et al. 2023

Front. Physiol.

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SLIT ligand and its receptor ROBO were initially recognized for their role in axon guidance in central nervous system development. In recent years, as research has advanced, the role of the SLIT-ROBO signaling pathway has gradually expanded from axonal repulsion to cell migration, tumor development, angiogenesis, and bone metabolism. As a secreted protein, SLIT regulates various pathophysiological processes in the kidney, such as proinflammatory responses and fibrosis progression. Many studies have shown that SLIT-ROBO is extensively involved in various aspects of kidney development and maintenance of structure and function. The SLIT-ROBO signaling pathway also plays an important role in different types of kidney disease. This article reviews the advances in the study of the SLIT-ROBO pathway in various renal pathophysiological and kidney disorders and proposes new directions for further research in this field.

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Proteolytic cleavage of Slit by the Tolkin protease converts an axon repulsion cue to an axon growth cue in vivo

Cited by 9 publications

References 74 publications

Psi promotes Drosophila wing growth via direct transcriptional activation of cell cycle targets and repression of growth inhibitors

Psi promotes Drosophila wing growth via direct transcriptional activation of cell cycle targets and repression of growth inhibitors

Egr-2 coordinates intestinal remodeling by promoting midline patterning and pharynx regeneration in planarians

Role of the SLIT-ROBO signaling pathway in renal pathophysiology and various renal diseases

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