Decrease, GLI1/2 translocation leads to Decrease, GLI1/2 target gene expression

The Glioma-associated onocogene (Gli) family of zinc finger transcription factors (Gli1, Gli2, Gli3) are the primarily downstream effectors of the Hedgehog (HH) signaling cascade. When HH ligand binds to Patched (PTCH), its’ inhibition on SMO is relieved. SMO this then able to accumulate to the tip of primary cilium in its’ active form (Corbit, Aanstad et al. 2005, Rohatgi, Milenkovic et al. 2007, Kim, Kato et al. 2009). SMO causes the GLI family to become dislodged from their complex with the negative regulator of HH signaling, Suppressor of Fused (Sufu) (Kogerman, Grimm et al. 1999, Pearse, Collier et al. 1999, Stone, Murone et al. 1999, Tukachinsky, Lopez et al. 2010). The GLI-Sufu complex maintains retention of Gli in the cytosol allowing for exposure to phosphorylation via protein kinase A (PKA) which inhibits downstream signal transduction  (Tuson, He et al. 2011). When SMO is activated, the GLI2/3-Sufu complex is dismantled allowing for retrograde transport of GLI back into the nucleus (Kim, Kato et al. 2009). This relocation then leads to signaling to effectors resulting in the activation of the GLI transcription factors and the subsequent induction of SHH target gene expression (Alexandre, Jacinto et al. 1996, Von Ohlen and Hooper 1997).

The GLI family is found in both a long activator form (GliA) or a proteolytically cleaved repressor form (GliR). Current understanding is that Gli3 functions primarily as a repressor while Gli1 and Gli2 function mainly as activators of the pathway and that recruitment of SMO to the cilium leads to an increase in the ratio of GliA:GliR (Hui and Angers 2011, Liu 2016). Downstream transcription is primarily activated by Gli2 and repressed by Gli3 (Wang, Fallon et al. 2000, Bai, Auerbach et al. 2002, Persson, Stamataki et al. 2002). Gli1 serves primarily as an activator of transcription and works through amplification of the activated state (Park, Bai et al. 2000).

          Pubmed was used as the primary database for evidence collection. Searches are organized by the date and search terms used in the supplementary table. Search results were initially screened through review of the title and abstract for potential for data relating GLI translocation and GLI target gene expression. Each selected publication and its’ data were then examined to determine if support or lack thereof existed for this KER. Papers that did not show any data relating to this KER were discarded. The search terms used are organized below in Table 1.

Table 1: KER 2721 literature search

The quantitative understanding for this KER is low. Studies to investigate response-response relationship as well as time scale have not been conducted or were not found in the literature review. The empirical evidence presented establishes that disruption of SHH signaling results in the altered gene expression of SHH target genes. There is a need for more studies to address the dose-response and time course relationship of this linkage.

All presented evidence for the relationship is performed in mice. The relationship is biologically plausible in human, but to date no specific experiments have addressed this question. The SHH pathway is well understood to be fundamental to proper embryonic development and that aberrant SHH signaling during embryonic development can cause birth defects including orofacial clefts (OFCs). For this reason, this KER is applicable to the embryonic stage with a high level of confidence.