Regulation of expression of SLITs and ROBOs

Regulation of expression of SLITs and ROBOs Expression of SLIT and ROBO proteins is regulated at the level of transcription, translation and protein localization and stability. LIM-homeodomain transcription factors LHX2, LHX3, LHX4, LHX9 and ISL1 have so far been implicated in a cell type-dependent transcriptional regulation of ROBO1, ROBO2, ROBO3 and SLIT2 (Wilson et al. 2008, Marcos-Mondejar et al. 2012, Kim et al. 2016). Homeobox transcription factor HOXA2 is involved in transcriptional regulation of ROBO2 (Geisen et al. 2008). Transcription of SLIT1 during optic tract development in Xenopus is stimulated by FGF signaling and may also involve the transcription factor HOXA2, but the mechanism has not been established (Atkinson-Leadbeater et al. 2010). PAX6 and the homeodomain transcription factor NKX2.2 are also implicated in regulation of SLIT1 transcription (Genethliou et al. 2009). An RNA binding protein, MSI1, binds ROBO3 mRNA and promotes its translation, thus increasing ROBO3 protein levels (Kuwako et al. 2010). A poorly studied E3 ubiquitin ligase ZSWIM8 promotes degradation of ROBO3 (Wang et al. 2013). ROBO1 is protein half-life is increased via deubiquitination of ROBO1 by a ubiquitin protease USP33 (Yuasa-Kawada et al. 2009, Huang et al. 2015). Interaction of SLIT2 with DAG1 (dystroglycan) is important for proper localization of SLIT2 at the floor plate (Wright et al. 2012). Interaction of SLIT1 with a type IV collagen COL4A5 is important for localization of SLIT1 to the basement membrane of the optical tectum (Xiao et al. 2011).