ROBO2 and Associated Diseases
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Backgrounds of ROBO2
Roundabout guidance receptor 2 (ROBO2) is a member of the immunoglobulin superfamily and encodes a cell adhesion molecule involved in axonal guidance and neurogenesis. It is a receptor for the slit guidance ligand 2 (SLIT2) ligand, and SLIT2-ROBO2 signaling acts as a chemorepulsive guidance cue to control axon pathfinding and neuron migration during nervous system development. Slit2-Robo2 signaling is also crucial for the normal development of the kidney and urinary collecting system. ROBO2 has been recognized as one of the human congenital anomalies of the kidney and urinary tract (CAKUT) pathogenic genes. It is preferentially expressed in the islet1 reporter (Isl1SS) subset and inhibits branch growth and synaptogenesis. ROBO2 consists of three parts: the extracellular domain, transmembrane regions, and the intracellular region. It has been found to regulate different physiological functions and tumor development. ROBO2 acts as an anti-tumor gene and can potentially be a therapeutic target for pancreatic ductal adenocarcinoma (PDAC).
Functions of ROBO2
ROBO2 had important physiological functions, including cardiovascular tube formation, development of the urinary tract and kidney, and regulation of branching morphogenesis in pulmonary development. ROBO2 and its ligand SLIT2 also regulate Wolffian duct-nephrogenic cord separation before embryonic kidney induction and are required for normal ureteric bud outgrowth. ROBO2 plays important role in many tissues during development and particularly in the nervous system. It also plays an important role during early kidney development. The expression of ROBO2 in podocytes inhibited nephrin-induced actin polymerization, down-regulated non-muscular myosin IIA activity, and disrupted the adhesion stability of renal podocytes. The ROBO2 signaling pathway plays a negative regulatory role in nephrin-induced actin polymerization, reducing the F-actin skeleton in podocytes and podocytes adhesion. In nephrin-deficient mice, the loss of the ROBO2 signaling pathway can alleviate podocytes' foot process defects.
Fig.1 Robo2-dependent morphogenesis in trigeminal sensory neurons. (Pan, 2012)
Expression of ROBO2 in Diseases
- ROBO2 loss-of-function mutations in zebrafish and mice result in retinal and commissural pathfinding defects, respectively.
- ROBO2 mutation can lead to various CAKUT phenotypes, such as unilateral or bilateral vesicoureteric reflux (VUR), posterior urethral valve (PUV), ureteropelvic junction obstruction, and multicystic dysplastic kidney.
- ROBO2 is dysregulated in various cancers such as acute myelogenous leukemia, prostate cancer, colorectal cancer, gastric carcinoma, ovarian cancer, and breast cancer. ROBO2 expression was lower in the pancreatic cancer cell lines. Downregulation of ROBO2 promoted proliferation, migration, and invasion in vitro and accelerated tumor growth in vivo. The functions and mechanisms of ROBO2 in tumor progression are gradually being recognized.
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Reference
- Pan, Y.A.; et al. Robo2 determines subtype-specific axonal projections of trigeminal sensory neurons. Development. 2012, 139(3): 591-600.
