Roundabout family

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Roundabout
Mutant Robo Receptors and Axonal Midline Crossing.jpg
Mutant Robo Receptors and Axonal Midline Crossing
Identifiers
SymbolRoundabout
Membranome 21
roundabout
Identifiers
Organism Drosophila melanogaster
Symbolrobo
Alt. symbolsrobo1
Entrez 37603
RefSeq (mRNA) NM_057551.3
RefSeq (Prot) NP_476899.1
UniProt Q7KVK3
Other data
Chromosome 2R: 18.58 - 18.59 Mb
Search for
Structures Swiss-model
Domains InterPro
leak
Identifiers
Organism Drosophila melanogaster
Symbollea
Alt. symbolsrobo2
Entrez 44522
RefSeq (mRNA) NM_080531.3
RefSeq (Prot) NP_536792.2
UniProt Q9VQ08
Other data
Chromosome 2L: 1.37 - 1.43 Mb
Search for
Structures Swiss-model
Domains InterPro
robo3
Identifiers
Organism Drosophila melanogaster
Symbolrobo3
Alt. symbolsrobo3
Entrez 33314
RefSeq (mRNA) NM_134748.2
RefSeq (Prot) NP_608592.2
UniProt Q9VPZ7
Other data
Chromosome 2L: 1.25 - 1.3 Mb
Search for
Structures Swiss-model
Domains InterPro
roundabout homolog 1
Identifiers
Symbol ROBO1
NCBI gene 6091
HGNC 10249
OMIM 602430
RefSeq NM_002941
UniProt Q9Y6N7
Other data
Locus Chr. 3 p12.3
Search for
Structures Swiss-model
Domains InterPro
roundabout homolog 2
Identifiers
Symbol ROBO2
NCBI gene 6092
HGNC 10250
OMIM 602431
RefSeq XM_031246
UniProt Q9HCK4
Other data
Locus Chr. 3 p12.3
Search for
Structures Swiss-model
Domains InterPro
roundabout homolog 3
Identifiers
Symbol ROBO3
NCBI gene 64221
HGNC 13433
OMIM Q96MS0
RefSeq XM_370663
UniProt Q96MS0
Other data
Locus Chr. 11 q24
Search for
Structures Swiss-model
Domains InterPro
roundabout homolog 4
Identifiers
Symbol ROBO4
NCBI gene 54538
HGNC 17985
OMIM 607528
RefSeq NM_019055
UniProt Q8WZ75
Other data
Locus Chr. 11 q24.2
Search for
Structures Swiss-model
Domains InterPro

The Roundabout (Robo) family of proteins are single-pass transmembrane receptors that are highly conserved across many branches of the animal kingdom, from C. elegans to humans. [1] They were first discovered in Drosophila , through a mutant screen for genes involved in axon guidance. The Drosophila roundabout mutant was named after its phenotype, which resembled the circular traffic junctions (see roundabout). [2] The Robo receptors are most well known for their role in the development of the nervous system, where they have been shown to respond to secreted Slit ligands. [2] [3] [4] One well-studied example is the requirement for Slit-Robo signaling in regulation of axonal midline crossing. Slit-Robo signaling is also critical for many neurodevelopmental processes including formation of the olfactory tract, the optic nerve, and motor axon fasciculation. [5] [6] In addition, Slit-Robo signaling contributes to cell migration and the development of other tissues such as the lung, kidney, liver, muscle and breast. [7] [8] Mutations in Robo genes have been linked to multiple neurodevelopmental disorders in humans.

Contents

Discovery

A large-scale screen of the Drosophila genome for mutants that exhibited axon guidance defects led to the discovery of the roundabout (robo) mutation. [9] In robo mutants, axons were observed to inappropriately cross and recross the midline. It was subsequently found that the secreted protein Slit was the ligand for the Roundabout receptor. [10] Vertebrate Slit proteins were identified shortly after, and were shown to bind both vertebrate and Drosophila Robo receptors and to mediate axonal repulsion of spinal cord explants. [4] It was several more years before a functional analysis of the vertebrate Slit and Robo mutants was performed; this analysis demonstrated that Slit-Robo signaling regulates commissural axon guidance in vertebrates as well. [11] While the vertebrate receptors Robo1 and Robo2 signal repulsion in response to Slit to prevent inappropriate midline crossing, a novel function for Robo3/Rig1 was discovered; unlike the other Robo receptors, it is required to promote midline crossing. [12]

Evolution of the family members

Phylogenetic analysis reveals that all Robo receptors have evolved from a common ancestral protein, with many subsequent diversification events occurring independently in different lineages. [1] The Robo gene was initially identified in Drosophila and has since been cloned in various species including mice and humans. [13] Drosophila have three Robo receptors: Robo1, Robo2, and Robo3. [14] [15] In vertebrates, four Robo receptors have been identified: Robo1, Robo2, Robo3/Rig-1, and Robo4/Magic Roundabout. [16]

Genes

Location

In humans, Robo1 and Robo2 are located on chromosome 3p12.3, while Robo3 and Robo4 are found on chromosome 11p24.2. In mice, the corresponding Robo genes 1 and 2 are found on chromosome 16 and Robo genes 3 and 4 are located on chromosome 9.

Alternative splicing

In vertebrates, Robo1 undergoes complex alternative splicing, generating several isoforms including DUTT1, a variant that has been identified as a tumor suppressor gene. [17] Vertebrate Robo3/Rig1 is also alternatively spliced; its two splice products are expressed at different times during commissural axon guidance, and have opposing activities. [18]

Tissue distribution

In humans, Robo1 is expressed generally throughout the central nervous system. [17] Robo2 is enriched in most regions of the adult and fetal brain, as well as in the adult ovary. Intermediate expression of Robo2 is seen in the fetal liver and adult lung, kidney, spleen, testes, and spinal cord. [19] Robo3/Rig1 is found in the hindbrain and spinal cord. [20] Robo4 is expressed in the heart, liver, lungs, kidney, muscle, small intestine, endothelial cells, and largely in the placenta. [21]

Protein structure

Each member of the Robo family has a similar structure, consisting of five immunoglobulin-like domains, three fibronectin type III (FN3) repeats, a transmembrane domain, and a cytoplasmic domain with up to four conserved motifs (CC0-3). In all identified Robo receptors except for vertebrate Robo4, the Ig1 and Ig2 domains have been evolutionarily conserved and are crucial for binding to Slit ligands. Robo4 is unusual as it only contains two Ig and FN3 domains. However, recent research proposes that the vertebrate Slit2 protein can in fact bind to Robo4. [22]

Function

Robo-Slit Interactions and Axonal Midline Guidance Robo-Slit Interactions and Axonal Midline Guidance.jpg
Robo-Slit Interactions and Axonal Midline Guidance

Axonal guidance

In bilaterian animals, including insects and mammals, most axons in the CNS cross the midline during nervous system development. The Robo proteins are critical regulators of midline crossing across species. In Drosophila embryos, Robo1 and Robo2 are required to keep ipsilaterally projecting axons from inappropriately crossing the midline, and to prevent contralateral axons from remaining stuck at the midline. Robo3, while it also binds Slit, does not appear to play a major role in regulating midline crossing. Instead, it is required for the lateral pathway selection of axons after crossing. [14] Robo2 also contributes to lateral pathway formation.

In the vertebrate spinal cord, Robo1 and Robo2 are expressed on commissural axons and act as repulsive receptors for the Slit ligands expressed by floor plate cells located at the midline. [11] In contrast, Robo3/Rig1 is required for midline crossing, and acts in part by antagonizing Slit-mediated repulsion by Robo1 and Robo2. [23]

Robo receptors have also been shown to be crucial regulators of many other axon pathfinding decisions during development, including the projection of axons in the optic tract and the olfactory epithelium. [5] [6]

Guidance of non-neural cells

The Robo gene family contributes to the guidance and migration of non-neural cells, including neuronal precursor cells, muscle cells, tracheal cells, Langerhans cells, and vascular smooth muscle cells.

Glioma invasion and migration inhibition

Robo1 is thought to play a role in the inhibition of glioma invasion and migration. Glioblastoma cells grow away from areas that contain high concentrations of Slit2 and its receptor Robo1, suggesting that the Robo1/Slit2 complex can serve as a chemorepellent for glioma cells, inhibiting the invasion and migration of the tumor cells.

Actin cytoskeleton regulation

The binding of Slit to Robo receptors leads to reorganization of the actin cytoskeleton. Actin polymerization is regulated by several adaptor proteins that can bind to the cytoplasmic motifs of the Robo receptors. In Drosophila, several signaling proteins downstream of Robo1 have been identified, including Enabled, Son of Sevenless (SOS), Rac, and Dock. [24] [25] [26] It is thought that activation of Robo1 by Slit leads to increased depolymerization of actin, resulting in growth cone collapse. It remains unclear how Drosophila Robo2 and Robo3 signal, although multiple studies suggest that they have distinct signaling capabilities that cannot be recapitulated by Robo1. [27] [28]

Midline attraction and Robo3

The vertebrate Robo3/Rig1 homolog is a more distant relative of the Robo gene family, and is thought to play a distinct role in axonal guidance. [16] [29] Robo3/Rig1 is alternatively spliced to generate a protein that inhibits Robo1/2-mediated repulsion, effectively leading to the promotion of midline crossing. [23] The exact mechanism by which Robo3 achieves this anti-repulsive activity is unknown. [29]

Clinical applications and areas of research

Angiogenesis and tumor suppression

The Robo4 receptor has been linked to angiogenesis in both mice and zebrafish. It is also present in human microvascular endothelial cells (HMVEC) and human umbilical vein endothelial cells (HUVEC). Exposure of Robo4 to Slit2 inhibits angiogenesis. However, exposure to a protein that inhibits Slit2 also inhibits angiogenesis. [30] Due to these inconclusive results, the role of Robo4 in blood vessel growth is not completely understood.

Robo1 has been linked to cancerous tumor growth and suppression. The Slit2/Robo1 pathway has been associated with tumor angiogenesis, leading to subsequent tumor growth. Slit2 proteins have been identified in several varieties of tumors, including melanoma, breast cancer, small cell lung cancer, and bladder cancer. Furthermore, inhibition of the Slit2/Robo1 pathway via R5 and RoboN reduced tumor mass and volume, while also reducing microvessel density. [31] However, Slit2 proteins have not been identified in all kinds of tumors, and other research suggests that Slit-2 expression may suppress tumors in small cell lung cancer and breast cancer. [30]

Dyslexia

The Robo1 protein is thought to be associated with dyslexia, possibly through chromosomal translocation. [32] The role of Robo1 in regards to dyslexia is not fully understood at this time.

Psychopathy

Recently, a genome-wide linkage study by Viding and colleagues (2010)reported that the Robo2 gene could be involved in developmental disorders such as psychopathy.

Robo3/Rig1 and HGPPS

A defect in the Robo3/Rig1 protein results in horizontal gaze palsy with progressive scoliosis (HGPPS), a rare genetic disorder. HGPPS is characterized by a lack of horizontal eye movement within the socket (although vertical movement remains unaffected) and the gradual curvature of the spine throughout development. [33] [34] The disorder is caused by a genetic mutation on chromosome 11, and is autosomal recessive. [35] During normal brain development, Robo3/Rig1 decreases sensitivity of Robo1 to Slit proteins, allowing the axon to grow past the midline. [34] This process allows axons to cross to the other side of the brain, which is crucial for motor function as well as sensory processing. In patients with HGPPS, the absence of Robo3/Rig1 prevents axons in the corticospinal tract and the trochlear nerve [33] from growing past the midline. This abnormal growth of the hindbrain and spinal cord manifests itself as the symptoms associated with HGPPS.

Related Research Articles

<span class="mw-page-title-main">Optic chiasm</span> Part of the brain where the optic nerves cross

In neuroanatomy, the optic chiasm, or optic chiasma, is the part of the brain where the optic nerves cross. It is located at the bottom of the brain immediately inferior to the hypothalamus. The optic chiasm is found in all vertebrates, although in cyclostomes, it is located within the brain.

<span class="mw-page-title-main">Retinal ganglion cell</span> Type of cell within the eye

A retinal ganglion cell (RGC) is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and retina amacrine cells. Retina amacrine cells, particularly narrow field cells, are important for creating functional subunits within the ganglion cell layer and making it so that ganglion cells can observe a small dot moving a small distance. Retinal ganglion cells collectively transmit image-forming and non-image forming visual information from the retina in the form of action potential to several regions in the thalamus, hypothalamus, and mesencephalon, or midbrain.

<span class="mw-page-title-main">DSCAM</span> Protein-coding gene in the species Homo sapiens

DSCAM and Dscam are both abbreviations for Down syndrome cell adhesion molecule. In humans, DSCAM refers to a gene that encodes one of several protein isoforms.

Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.

<span class="mw-page-title-main">Netrin</span> Class of proteins involved in axon guidance

Netrins are a class of proteins involved in axon guidance. They are named after the Sanskrit word "netr", which means "one who guides". Netrins are genetically conserved across nematode worms, fruit flies, frogs, mice, and humans. Structurally, netrin resembles the extracellular matrix protein laminin.

<span class="mw-page-title-main">Floor plate</span> Embryonic structure

The floor plate is a structure integral to the developing nervous system of vertebrate organisms. Located on the ventral midline of the embryonic neural tube, the floor plate is a specialized glial structure that spans the anteroposterior axis from the midbrain to the tail regions. It has been shown that the floor plate is conserved among vertebrates, such as zebrafish and mice, with homologous structures in invertebrates such as the fruit fly Drosophila and the nematode C. elegans. Functionally, the structure serves as an organizer to ventralize tissues in the embryo as well as to guide neuronal positioning and differentiation along the dorsoventral axis of the neural tube.

<span class="mw-page-title-main">Ephrin receptor</span> Protein family

Eph receptors are a group of receptors that are activated in response to binding with Eph receptor-interacting proteins (Ephrins). Ephs form the largest known subfamily of receptor tyrosine kinases (RTKs). Both Eph receptors and their corresponding ephrin ligands are membrane-bound proteins that require direct cell-cell interactions for Eph receptor activation. Eph/ephrin signaling has been implicated in the regulation of a host of processes critical to embryonic development including axon guidance, formation of tissue boundaries, cell migration, and segmentation. Additionally, Eph/ephrin signaling has been identified to play a critical role in the maintenance of several processes during adulthood including long-term potentiation, angiogenesis, and stem cell differentiation and cancer.

Semaphorins are a class of secreted and membrane proteins that were originally identified as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. Semaphorins are usually cues to deflect axons from inappropriate regions, especially important in the neural system development. The major class of proteins that act as their receptors are called plexins, with neuropilins as their co-receptors in many cases. The main receptors for semaphorins are plexins, which have established roles in regulating Rho-family GTPases. Recent work shows that plexins can also influence R-Ras, which, in turn, can regulate integrins. Such regulation is probably a common feature of semaphorin signalling and contributes substantially to our understanding of semaphorin biology.

Pioneer axon is the classification given to axons that are the first to grow in a particular region. They originate from pioneer neurons, and have the main function of laying down the initial growing path that subsequent growing axons, dubbed follower axons, from other neurons will eventually follow.

<span class="mw-page-title-main">Ephrin</span> Family of proteins

Ephrins are a family of proteins that serve as the ligands of the Eph receptor. Eph receptors in turn compose the largest known subfamily of receptor protein-tyrosine kinases (RTKs).

<span class="mw-page-title-main">Neuropilin 1</span> Protein-coding gene in the species Homo sapiens

Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene. In humans, the neuropilin 1 gene is located at 10p11.22. This is one of two human neuropilins.

<span class="mw-page-title-main">SLIT2</span> Protein-coding gene in the species Homo sapiens

Slit homolog 2 protein is a protein that in humans is encoded by the SLIT2 gene.

<span class="mw-page-title-main">ROBO1</span> Protein-coding gene in the species Homo sapiens

Roundabout homolog 1 is a protein that in humans is encoded by the ROBO1 gene.

<span class="mw-page-title-main">Netrin 1</span> Protein-coding gene in the species Homo sapiens

Netrin-1 is a protein that in humans is encoded by the NTN1 gene.

<span class="mw-page-title-main">ROBO2</span> Protein-coding gene in the species Homo sapiens

Roundabout homolog 2 is a protein that in humans is encoded by the ROBO2 gene.

Slit is a family of secreted extracellular matrix proteins which play an important signalling role in the neural development of most bilaterians. While lower animal species, including insects and nematode worms, possess a single Slit gene, humans, mice and other vertebrates possess three Slit homologs: Slit1, Slit2 and Slit3. Human Slits have been shown to be involved in certain pathological conditions, such as cancer and inflammation.

<span class="mw-page-title-main">Immunoglobulin I-set domain</span>

I-set domains are found in several cell adhesion molecules, including vascular (VCAM), intercellular (ICAM), neural (NCAM) and mucosal addressin (MADCAM) cell adhesion molecules, as well as junction adhesion molecules (JAM). I-set domains are also present in several other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signalling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

Slit-Robo is the name of a cell signaling protein complex with many diverse functions including axon guidance and angiogenesis.

<span class="mw-page-title-main">Tropic cues involved in growth cone guidance</span>

The growth cone is a highly dynamic structure of the developing neuron, changing directionality in response to different secreted and contact-dependent guidance cues; it navigates through the developing nervous system in search of its target. The migration of the growth cone is mediated through the interaction of numerous trophic and tropic factors; netrins, slits, ephrins and semaphorins are four well-studied tropic cues (Fig.1). The growth cone is capable of modifying its sensitivity to these guidance molecules as it migrates to its target; this sensitivity regulation is an important theme seen throughout development.

Alain Chédotal is a French researcher specialising in the development of neural circuits. He has been a member of the French Academy of sciences since 2017.

References

[36]

  1. 1 2 Evans TA, Bashaw GJ (March 2012). "Slit/Robo-mediated axon guidance in Tribolium and Drosophila: divergent genetic programs build insect nervous systems". Dev. Biol. 363 (1): 266–78. doi:10.1016/j.ydbio.2011.12.046. PMC   4128232 . PMID   22245052.
  2. 1 2 Kidd T, Brose K, Mitchell KJ, Fetter RD, Tessier-Lavigne M, Goodman CS, Tear G (January 1998). "Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors". Cell. 92 (2): 205–15. doi: 10.1016/S0092-8674(00)80915-0 . PMID   9458045. S2CID   2036419.
  3. ↑ Battye R, Stevens A, Jacobs JR (June 1999). "Axon repulsion from the midline of the Drosophila CNS requires slit function". Development. 126 (11): 2475–81. doi:10.1242/dev.126.11.2475. PMID   10226006.
  4. 1 2 Brose K, Bland KS, Wang KH, Arnott D, Henzel W, Goodman CS, Tessier-Lavigne M, Kidd T (March 1999). "Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance". Cell. 96 (6): 795–806. doi: 10.1016/S0092-8674(00)80590-5 . PMID   10102268. S2CID   16301178.
  5. 1 2 Li HS, Chen JH, Wu W, Fagaly T, Zhou L, Yuan W, Dupuis S, Jiang ZH, Nash W, Gick C, Ornitz DM, Wu JY, Rao Y (March 1999). "Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons". Cell. 96 (6): 807–18. doi: 10.1016/S0092-8674(00)80591-7 . PMID   10102269.
  6. 1 2 Fricke C, Lee JS, Geiger-Rudolph S, Bonhoeffer F, Chien CB (April 2001). "astray, a zebrafish roundabout homolog required for retinal axon guidance". Science. 292 (5516): 507–10. Bibcode:2001Sci...292..507F. doi:10.1126/science.1059496. PMID   11313496. S2CID   45460824.
  7. ↑ Englund C, Steneberg P, Falileeva L, Xylourgidis N, Samakovlis C (November 2002). "Attractive and repulsive functions of Slit are mediated by different receptors in the Drosophila trachea". Development. 129 (21): 4941–51. doi:10.1242/dev.129.21.4941. PMID   12397103.
  8. ↑ Kramer SG, Kidd T, Simpson JH, Goodman CS (April 2001). "Switching repulsion to attraction: changing responses to slit during transition in mesoderm migration". Science. 292 (5517): 737–40. Bibcode:2001Sci...292..737K. doi:10.1126/science.1058766. PMID   11326102. S2CID   44802898.
  9. ↑ Seeger M, Tear G, Ferres-Marco D, Goodman CS (March 1993). "Mutations affecting growth cone guidance in Drosophila: genes necessary for guidance toward or away from the midline". Neuron. 10 (3): 409–26. doi:10.1016/0896-6273(93)90330-T. PMID   8461134. S2CID   21594847.
  10. ↑ Kidd T, Bland KS, Goodman CS (March 1999). "Slit is the midline repellent for the robo receptor in Drosophila". Cell. 96 (6): 785–94. doi: 10.1016/S0092-8674(00)80589-9 . PMID   10102267. S2CID   15284604.
  11. 1 2 Long H, Sabatier C, Ma L, Plump A, Yuan W, Ornitz DM, Tamada A, Murakami F, Goodman CS, Tessier-Lavigne M (April 2004). "Conserved roles for Slit and Robo proteins in midline commisural axon guidance". Neuron. 42 (2): 213–23. doi: 10.1016/S0896-6273(04)00179-5 . PMID   15091338.
  12. ↑ Sabatier C, Plump A, Ma L, Brose K, Tamada A, Murakami F, Lee E, Tessier-Lavigne M (April 2004). "The divergent Robo family protein rig-1/Robo3 is a negative regulator of Slit responsiveness required for midline crossing by commisural axons". Cell. 117 (2): 157–69. doi: 10.1016/S0092-8674(04)00303-4 . PMID   15084255. S2CID   12921753.
  13. ↑ Fujiwara M, Ghazizadeh M, Kawanami O (May 2006). "Potential role of the Slit/Robo signal pathway in angiogenesis". Vasc Med. 11 (2): 115–21. doi:10.1191/1358863x06vm658ra. PMID   16886842. S2CID   26996188.
  14. 1 2 Simpson JH, Bland KS, Fetter RD, Goodman CS (December 2000). "Short-range and long-range guidance by Slit and its Robo receptors: a combinatorial code of Robo receptors controls lateral position". Cell. 103 (7): 1019–32. doi: 10.1016/S0092-8674(00)00206-3 . PMID   11163179. S2CID   7251670.
  15. ↑ Rajagopalan S, Vivancos V, Nicolas E, Dickson BJ (December 2000). "Selecting a longitudinal pathway: Robo receptors specify the lateral position of axons in the Drosophila CNS". Cell. 103 (7): 1033–45. doi: 10.1016/S0092-8674(00)00207-5 . PMID   11163180. S2CID   17703851.
  16. 1 2 Xu Y, Li WL, Fu L, Gu F, Ma YJ (December 2010). "Slit2/Robo1 signaling in glioma migration and invasion". Neurosci Bull. 26 (6): 474–8. doi:10.1007/s12264-010-0730-9. PMC   5560338 . PMID   21113198.
  17. 1 2 Online Mendelian Inheritance in Man (OMIM): 602430
  18. ↑ Chen S, Gore BB, Long H, Ma L, Tessier-Lavigne M (May 2008). "Alternative splicing of the Robo3 axon guidance receptor governs the midline switch from attraction to repulsion". Neuron. 58 (3): 325–32. doi: 10.1016/j.neuron.2008.02.016 . PMID   18466743. S2CID   7214473.
  19. ↑ Online Mendelian Inheritance in Man (OMIM): 602431
  20. ↑ Online Mendelian Inheritance in Man (OMIM): 608630
  21. ↑ Online Mendelian Inheritance in Man (OMIM): 607528
  22. ↑ Dickinson RE, Duncan, W C. (25 January 2010). "The SLIT-ROBO pathway: a regulator of cell function with implications for the reproductive system". Reproduction. 139 (4): 697–704. doi:10.1530/REP-10-0017. PMC   2971463 . PMID   20100881.
  23. 1 2 Marillat V, Sabatier C, Failli V, Matsunaga E, Sotelo C, Tessier-Lavigne M, Chédotal A (July 2004). "The slit receptor Rig-1/Robo3 controls midline crossing by hindbrain precerebellar neurons and axons". Neuron. 43 (1): 69–79. doi: 10.1016/j.neuron.2004.06.018 . PMID   15233918. S2CID   18762312.
  24. ↑ Bashaw GJ, Kidd T, Murray D, Pawson T, Goodman CS (June 2000). "Repulsive axon guidance: Abelson and Enabled play opposing roles downstream of the roundabout receptor". Cell. 101 (7): 703–15. doi: 10.1016/S0092-8674(00)80883-1 . PMID   10892742. S2CID   2715852.
  25. ↑ Fan X, Labrador JP, Hing H, Bashaw GJ (September 2003). "Slit stimulation recruits Dock and Pak to the roundabout receptor and increases Rac activity to regulate axon repulsion at the CNS midline". Neuron. 40 (1): 113–27. doi: 10.1016/S0896-6273(03)00591-9 . PMID   14527437. S2CID   1707716.
  26. ↑ Hu H, Li M, Labrador JP, McEwen J, Lai EC, Goodman CS, Bashaw GJ (March 2005). "Cross GTPase-activating protein (CrossGAP)/Vilse links the Roundabout receptor to Rac to regulate midline repulsion". Proc. Natl. Acad. Sci. U.S.A. 102 (12): 4613–8. Bibcode:2005PNAS..102.4613H. doi: 10.1073/pnas.0409325102 . PMC   555501 . PMID   15755809.
  27. ↑ Spitzweck B, Brankatschk M, Dickson BJ (February 2010). "Distinct protein domains and expression patterns confer divergent axon guidance functions for Drosophila Robo receptors". Cell. 140 (3): 409–20. doi: 10.1016/j.cell.2010.01.002 . PMID   20144763.
  28. ↑ Evans TA, Bashaw GJ (March 2010). "Functional diversity of Robo receptor immunoglobulin domains promotes distinct axon guidance decisions". Curr. Biol. 20 (6): 567–72. Bibcode:2010CBio...20..567E. doi:10.1016/j.cub.2010.02.021. PMC   4078746 . PMID   20206526.
  29. 1 2 Guthrie S (August 2004). "Axon guidance: mice and men need Rig and Robo". Curr. Biol. 14 (15): R632–4. Bibcode:2004CBio...14.R632G. doi: 10.1016/j.cub.2004.07.050 . PMID   15296783.
  30. 1 2 Klagsbrun M, Eichmann A (2005). "A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis". Cytokine Growth Factor Rev. 16 (4–5): 535–48. doi:10.1016/j.cytogfr.2005.05.002. PMID   15979925.
  31. ↑ Wang B, Xiao Y, Ding BB, Zhang N, Yuan X, Gui L, Qian KX, Duan S, Chen Z, Rao Y, Geng JG (July 2003). "Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity". Cancer Cell. 4 (1): 19–29. doi: 10.1016/S1535-6108(03)00164-8 . PMID   12892710.
  32. ↑ Galaburda AM, LoTurco J, Ramus F, Fitch RH, Rosen GD (October 2006). "From genes to behavior in developmental dyslexia". Nat. Neurosci. 9 (10): 1213–7. doi:10.1038/nn1772. PMID   17001339. S2CID   1807348.
  33. 1 2 Purves D (2011). Neuroscience. Sunderland, Mass: Sinauer Associates, Inc. ISBN   978-0-87893-695-3.
  34. 1 2 Butcher J (June 2004). "Mutations in ROBO3 cause HGPPS". Lancet Neurol. 3 (6): 328. doi:10.1016/S1474-4422(04)00786-0. PMID   15176408. S2CID   39054237.
  35. ↑ "Horizontal gaze palsy with progressive scoliosis" . Retrieved 2012-04-17.
  36. ↑ 36. Hauptman G, Reichert MC, Abdal Rhida MA, Evans TA. Characterization of enhancer fragments in Drosophila robo2. Fly (Austin). 2022 Dec;16(1):312-346. doi: 10.1080/19336934.2022.2126259. PMID 36217698; PMCID: PMC9559326.
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