Meta-Biol

• Pathways

The Roundabout (ROBO) family encodes transmembrane receptors that regulate axonal guidance and cell migration. The major function of the Robo receptors is to mediate repulsion of the navigating growth cones. There are four human Robo homologues, ROBO1, ROBO2, ROBO3 and ROBO4. Most of the ROBOs have the similar ectodomain architecture as the cell adhesion molecules, with five Ig domains followed by three FN3 repeats, except for ROBO4. ROBO4 has two Ig and two FN3 repeats. The cytoplasmic domains of ROBO receptors are in general poorly conserved. However, there are four short conserved cytoplasmic sequence motifs, named CC0-3, that serve as binding sites for adaptor proteins. The ligands for the human ROBO1 and ROBO2 receptors are the three SLIT proteins SLIT1, SLIT2, and SLIT3; all of the SLIT proteins contain a tandem of four LRR (leucine rich repeat) domains at the N-terminus, termed D1-D4, followed by six EGF (epidermal growth factor)-like domains, a laminin G like domain (ALPS), three EGF-like domains, and a C-terminal cysteine knot domain. Most SLIT proteins are cleaved within the EGF-like region by unknown proteases (reviewed by Hohenster 2008, Ypsilanti and Chedotal 2014, Blockus and Chedotal 2016). NELL2 is a ligand for ROBO3 (Jaworski et al. 2015).

SLIT protein binding modulates ROBO interactions with the cytosolic adaptors. The cytoplasmic domain of ROBO1 and ROBO2 determines the repulsive responses of these receptors. Based on the studies from both invertebrate and vertebrate organisms it has been inferred that ROBO induces growth cone repulsion by controlling cytoskeletal dynamics via either Abelson kinase (ABL) and Enabled (Ena), or RAC1 activity (reviewed by Hohenster 2008, Ypsilanti and Chedotal 2014, Blockus and Chedotal 2016). While there is some redundancy in the function of ROBO receptors, ROBO1 is implicated as the predominant receptor for axon guidance in ventral tracts, and ROBO2 is the predominant receptor for axon guidance in dorsal tracts. ROBO2 also repels neuron cell bodies from the floor plate (Kim et al. 2011).

In addition to regulating axon guidance, ROBO1 and ROBO2 receptors are also implicated in regulation of proliferation and transition of primary to intermediate neuronal progenitors through a poorly characterized cross-talk with NOTCH-mediated activation of HES1 transcription (Borrell et al. 2012).

Thalamocortical axon extension is regulated by neuronal activity-dependent transcriptional regulation of ROBO1 transcription. Lower neuronal activity correlates with increased ROBO1 transcription, possibly mediated by the NFKB complex (Mire et al. 2012).

It is suggested that the homeodomain transcription factor NKX2.9 stimulates transcription of ROBO2, which is involved in regulation of motor axon exit from the vertebrate spinal code (Bravo-Ambrosio et al. 2012).

Of the four ROBO proteins, ROBO4 is not involved in neuronal system development but is, instead, involved in angiogenesis. The interaction of ROBO4 with SLIT3 is involved in proliferation, motility and chemotaxis of endothelial cells, and accelerates formation of blood vessels (Zhang et al. 2009).

Neurogenesis is the process by which neural stem cells give rise to neurons, and occurs both during embryonic and perinatal development as well as in specific brain lineages during adult life (reviewed in Gotz and Huttner, 2005; Yao et al, 2016; Kriegstein and Alvarez-Buylla, 2009).

As early steps towards capturing the array of processes by which a fertilized egg gives rise to the diverse tissues of the body, examples of several processes have been annotated. Aspects of processes involved in most developmental processes, transcriptional regulation of pluripotent stem cells, gastrulation, and activation of HOX genes during differentiation are annotated. More specialized processes include nervous system development , aspects of the roles of cell adhesion molecules in axonal guidance and myogenesis, transcriptional regulation in pancreatic beta cell, cardiogenesis, transcriptional regulation of granulopoeisis, transcriptional regulation of testis differentiation, transcriptional regulation of white adipocyte differentiation, and molecular events of "nodal" signaling, LGI-ADAM interactions, and keratinization.