The atypical homeoprotein Pbx1a participates in the axonal pathfinding of mesencephalic dopaminergic neurons
© Sgadò et al.; licensee BioMed Central Ltd. 2012
Received: 12 May 2012
Accepted: 2 July 2012
Published: 2 July 2012
The pre B-cell leukemia transcription factor 1 (Pbx1) genes belong to the three amino acid loop extension family of homeodomain proteins that form hetero-oligomeric complexes with other homeodomain transcription factors, thereby modulating target specificity, DNA binding affinity and transcriptional activity of their molecular associates.
Here, we provide evidence that Pbx1 is expressed in mesencephalic dopaminergic neurons from embryonic day 11 into adulthood and determines some of the cellular properties of this neuronal population. In Pbx1-deficient mice, the mesencephalic dopaminergic axons stall during mid-gestation at the border between di- and telencephalon before entering the ganglionic eminence, leading to a loose organization of the axonal bundle and partial misrouting. In Pbx1-deficient dopaminergic neurons, the high affinity netrin-1 receptor, deleted in colon cancer (DCC), is down-regulated. Interestingly, we found several conserved Pbx1 binding sites in the first intron of DCC, suggesting a direct regulation of DCC transcription by Pbx1.
The expression of Pbx1 in dopaminergic neurons and its regulation of DCC expression make it an important player in defining the axonal guidance of the midbrain dopaminergic neurons, with possible implications for the normal physiology of the nigro-striatal system as well as processes related to the degeneration of neurons during the course of Parkinson’s disease.
KeywordsAxonal outgrowth neurodegenerative disease Prep1 substantia nigra transcription factors ventral tegmentum
Deleted in colorectal cancer
Fibroblast growth factor 8
MEIS and KNOX subclass of the TALE superclass
PBC domain family of the TALE superclass
Pre B-cell leukemia homeobox
polymerase chain reaction
three amino acid loop extension
Pre B-cell leukemia transcription factor 1 (Pbx1) encodes a transcription factor, belonging to the PBC (Pbx1 to 4) subclass of the three amino acid loop extension (TALE) proteins characterized by an atypical homeodomain . Studies of the Pbx proteins and their Drosophila homolog Extradenticle (exd) revealed that they form stable complexes with other homeodomain transcription factors, such as Hox and Engrailed, as well as other non-homeodomain proteins . The interaction with Pbx modulates the target selectivity, the DNA binding affinity and the transcriptional activity of the associated homeoproteins . An example of the modulation of transcriptional activity by the Pbx transcription factors is the regulation of Fibroblast growth factor 8 (Fgf8) expression by the Engrailed transcription factors. A highly conserved region in the large intron of the Fgf8 gene contains an Engrailed/Pbx binding site. This part of the enhancer increases transcriptional activity by three to fourfold in the presence of embryonic nuclear extract containing the Engrailed proteins and Pbx1, and point mutations in the binding site inactivate it .
Pbx loss of function phenotype is to a large part a reflection of the phenotypic alterations observed after functional ablation of the associated molecular partner. In Drosophila, for example, embryos lacking exd (zygotic or maternal) show the typical homeotic transformations in the thoracic and abdominal segments that resemble the loss of function phenotypes of the Hox genes cooperating with exd, although their expression is unaltered . In mammals, the correlation between phenotypes of mutants deficient for Pbx1 and null mutants for the molecular partners is not as evident . Pbx genes have been implicated in development of the skeleton , pancreas , kidney, adrenal glands [9, 10], thymus , spleen  and in hematopoiesis . A number of homeodomain transcription factors play a major role in the development of all of these tissues and organs systems and may act as cofactors for Pbx genes.
We have previously demonstrated that the Engrailed genes are required for survival of the mesencephalic dopaminergic (mesDA) neurons [14, 15]. The survival function of Engrailed genes is unique to these neurons and is not shared with other neuronal populations expressing the genes, like the cerebellar granule cells [16, 17] or the V1 interneurons in the spinal cord . The cooperative binding to Pbx1 protein has already been shown to modulate the regulation of Fgf8 expression by the Engrailed genes, a crucial factor for the development of the mesDA neurons [4, 19, 20]. We therefore hypothesized that cooperative binding to Pbx proteins may modulate the target selectivity of the Engrailed genes in mesDA neurons.
We examined the expression and function of the Pbx genes in this neuronal population during development and show here that a splicing variant of Pbx1 Pbx1a, and one of the Prep genes, Prep1, are expressed by mesDA neurons. Furthermore, our analysis of Pbx1 mutant mice demonstrates a role of Pbx1 in axon guidance through the regulation of the netrin-1 receptor, deleted in colon cancer (DCC). Interestingly, despite increasing evidence of a cooperative function of Engrailed and Pbx transcription factors in vertebrates development [4, 21], we could not find a 1:1 correlation between Engrailed and Pbx1 mutants’ phenotype. In our case, a more detailed analysis of different single and compound mutants might be necessary to confirm our original hypothesis of a Pbx/Engrailed functional cooperative binding playing a significant role in the development and survival of mesDA.
Pbx1 expression in mesencephalic dopaminergic neurons
Pbx1 sub-cellular localization
The activity of PBC proteins is in part regulated by nuclear import, which is mediated by dimerization with homeoproteins of the MEINOX (MEIS and KNOX) sub-class, or by phosphorylation [24–27]. The MEIS subfamily of TALE proteins includes the products of the vertebrate Meis1-3, while the PREP subfamily includes the vertebrate Prep1 and Prep2. Exd and Pbx proteins have been shown to require MEIS/PREP for their nuclear import in specific cell contexts, such as limb mesenchymal cells in vertebrates or limb imaginal disc cells in flies [28–32].
Analysis of Pbx1 mutant mice
Analysis of mesencephalic dopaminergic markers in Pbx1 mutants
In order to assess whether Pbx1 deletion leads to the altered expression of other genes associated with mesDA neurons phenotype, concomitantly with the perturbation observed in DCC gene expression, we performed in situ hybridization on E15 embryos using probes specific for Nuclear receptor related 1 (Nurr1), En1, En2, LIM homeobox transcription factor 1-beta (Lmx1b), Pituitary homoebox 3 (Pitx3), TH Dopamine transporter (DAT) Dopa decarboxylase (AADC) Dopamine receptor 2 (DRD2) Ret oncogene (c-ret) Glial cell line-derived neurotrophic factor family receptor alpha 1 (GFR-α1), Aldehyde dehydrogenase family 1 subfamily A1 (Ahd2) and α-synuclein. None of them were altered in Pbx1−/− mutants.
Conversely, the absence of DCC expression in Pbx1-deficient mutant embryos suggested that DCC is a direct target of Pbx1. In order to investigate this hypothesis, we searched for putative Pbx1 binding sites in DCC regulatory region by in silico analysis. Our syntenic alignment of human, rat and mouse genomic sequences 20 kb upstream and 10 kb downstream of the start codon of the DCC gene in combination with the TRANSFAC database weight matrix for the Pbx1 consensus sequence revealed three conserved Pbx1 binding sites in the first intron of DCC at positions A: 775–786, 765–776, 761–772, B: 2059–2067, 2122–2130, 1996–2004 C: 2584–2592, 2645–2653, 2515–2523 bases downstream of the ATG in human, mouse and rat, respectively (data not shown). However no significant DNA enrichment was achieved by chromatin immunoprecipitation (ChIP) either with a specific Pbx1 antibody or with the pan-Pbx antibody (data not shown), indicating that regulation of DCC expression by Pbx1 is probably not direct.
We show here that Pbx1a is expressed in mesDA neurons from E11 into adulthood. During early embryogenesis, its expression in the neural tube is abundant, and becomes later confined in the ventral midbrain to only mesDA neurons. The co-expression of Pbx1a and Prep1 in mesDA neurons suggests that Pbx1 nuclear localization is achieved in this neuronal population through molecular association with Prep1. We, furthermore, show an aberrant mesDA axonal projection in Pbx1−/− embryos, which is likely the result of the loss of DCC expression. However we were not able to demonstrate direct Pbx1 binding on the three highly conserved Pbx1 binding sites in the first intron of DCC by ChIP.
A number of studies have shown molecular interactions between Pbx proteins and several other transcription factors and transcriptional co-regulators. The most studied Pbx partners are the Hox proteins. However, Pbx members form functional heterodimeric complexes with other homeoproteins, such as Engrailed and Pdx1, and other non-homeodomain transcription factors of the basic helix-loop-helix, forkhead and Smad family, as well as with members of the nuclear receptor superfamily [2, 6]. Pbx loss of function phenotype is very often correlated to the function of the associated partner. Pbx1-deficient mice die at E15.5, displaying severe hypoplasia (lungs, liver, stomach, gut, kidneys and pancreas), ectopia (thymus and kidneys) or aplasia (spleen, adrenal gland) of multiple organs, and widespread defects of the axial and appendicular skeleton . Although mice with Pbx1 targeted mutation exhibit some degree of homeotic transformations, they do not perfectly resemble mutants for Hox genes, their most studied partners. The same can be said for other Pbx mutants. Pbx3-deficient mice survive to term, but die soon after birth from central respiratory failure . Pbx1 and Pbx3 have overlapping embryonic expression domains and could therefore exhibit redundant functions. In contrast to Pbx1- and Pbx3-deficient mice, Pbx2-deficient mice are viable and display no apparent phenotype despite its broad expression . Therefore the phenotype of the Pbx targeted mutants could be the result of compensatory functions of other Pbx members and/or partial partner-independent functions [2, 6].
The phenotypical alterations in mesDA neurons of Pbx1-deficient mice can be considered in correlation to the well-described Engrailed phenotype in these cells. The targeted deletion of both Engrailed genes leads to severe tissue deletion in the mesencephalon and loss of mesDA neurons at birth . A more detailed analysis of these mutant mice revealed that the dopaminergic neurons are generated in the mesencephalic flexure, but die by E14 without extending axonal processes . MesDA neurons in Pbx1-deficent embryos survive beyond E14 and are able to extend axons; a phenotype that seems to diverge from the complete ablation of mesDA neurons observed in Engrailed double mutant embryos. Yet a cooperative function of Engrailed and Pbx1 cannot be excluded on the base of this sole phenotypic resemblance. Engrailed mutation show a gene-dose dependent effect on the survival of mesDA neurons  and no information have been reported about the axonal projections of mesDA neurons in other single or compound Engrailed mutants. Furthermore, our analysis does not exclude a redundant effect of other Pbx genes. The presence of Pbx3 mRNA expression in these neurons indicates the possibility of a compensatory effect in absence of Pbx1, therefore restoring the threshold Pbx proteins concentration required for a correct development.
We report here that Pbx1 loss of function leads to defasciculation and misrouting of mesDA axons in the border between di- and telencephalon. Since Pbx1 is expressed in mesDA neurons as well as in the developing target tissue , the axonal outgrowth phenotype of Pbx1-deficient mice could reflect alterations in either of the two. The unaltered expression of netrin-1 in the ganglionic eminence, the intact morphology of the tissue and the loss of DCC expression suggest that the mesDA axonal phenotype is likely attributable to a cell-autonomous function of Pbx1.
Several studies suggest that multiple cues collaborate to guide dopaminergic axons into a restricted domain through the diencephalon. Initially, migration of mesDA axons rostrally is determined by repulsion from a posterior source of semaphorin. Once in the diencephalon, mesDA axons are constrained in a narrow path established by multiple signals that keep axons from diverging ventrally or dorsally. The ventral boundary requires both Robo/Slit [48, 49] and Netrin/DCC [35, 36] opposing actions, as both slits repulsion and netrins attraction actions contribute to prevent dopaminergic axons from crossing the midline. Dorsal repulsion instead is likely mediated by attractive cues only, such as netrin and Sonic hedgehog [35, 49–51]. Finally, mesDA projections into the basal forebrain and cortex require an unusual attractive activity of semaphorin .
A recent analysis of DCC loss of function in vitro and in vivo demonstrated that DCC regulates neuronal precursor cell migration, axon guidance and axonal terminal arborization . Nevertheless, even in absence of DCC expression, mesDA axons are able to reach their target tissue . Differently from the previous report, however, in Pbx1-deficient embryos, loss of DCC expression has no effect on cell migration and seems to affect only long-range axon guidance. In Pbx1-deficent mice, axonal outgrowth is not affected until the mesDA neurons reach the border region between di- and telencephalon, and only at this point does Pbx1-mediated DCC/netrin signaling seem to be required. Unfortunately, Pbx1 mutant mice die at E15.5, preventing further analysis of the phenotype induced by the loss of DCC expression in these mice. No information is available on the embryonic phenotype of DCC mutants to be compared with those of Pbx1 mutants. Furthermore, analysis at later stages of the basal forebrain structures affected by abnormal nigro-striatal axonal targeting (dorsal striatum, olfactory tubercle, etc…) is not possible in Pbx1-mutants as complete maturation of dopaminergic innervations to the forebrain takes place between E15 and P0 [34, 53].
According to the Stein and Tessier-Lavigne ‘Hierarchical organization of guidance receptors’ model , activation of DCC by netrin, and concomitantly of Robo by Slit, leads to silencing of the attractive DCC-mediated netrin response without affecting its growth-stimulatory effect. Indeed, both DCC and Robo are expressed in mesDA neurons at developmental stages consistent with the defect observed in Pbx1 mutant embryos and could contribute to the observed phenotype [35, 36, 49]. Furthermore, a recent study indicated that loss of Slit/Robo signaling leads to widespread errors in mesDA axonal trajectories in the diencephalon, similar to those observed in Pbx1-deficient mice .
In this study, we show that Pbx1 and possibly its co-factor Prep1 are part of the transcriptional factor network that control a key step in mesDA neuronal differentiation by regulating the establishment of mesencephalic-striatal axonal projection. The axon guidance pathways are not just important in development of mesDA neurons they may regulate survival of this neuronal population throughout life, as suggested by genetic linkage studies and their connection to sporadic Parkinson’s disease [55, 56]. Therefore, Pbx1 may be important in determining the vulnerability of mesDA neurons to degeneration during the early phases of Parkinson’s disease.
Targeted mutation of Pbx1 and En1tauLacZ mice has previously been described [7, 23]. Pbx1+/− and En1+/tlZ adult mice were crossed into a C57/Bl6 background. The colony was maintained at the central animal facility at the University of Heidelberg. Experiments were carried out in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) for the care and use of experimental animals; all procedures were approved by the central animal facility at the University of Heidelberg. Each of the described phenotypes was found in all analyzed mutant animals (n ≥ 4).
In situ hybridization
Radioactive and digoxigenin in situ hybridizations have been previously described . The riboprobes corresponded to 1644 to 2277 of NM_183355 (Pbx1a), 1917 to 3049 of NM_008783 (Pbx1b), 1468 to 2264 of NM_017463 (Pbx2), 1665 to 2331 of NM_016768 (Pbx3) and 2780 to 3304 of NM_007831 (DCC). TH and En1 are described elsewhere .
All immunohistochemistry, including the whole mount staining, was performed as described  using rabbit and sheep anti-TH antibodies (AB152 and AB1542 EMD Millipore Inc., Billerica, MA, USA) at 1:1,000, rabbit anti-pan-Pbx antibody (sc-888 Santa Cruz Biotechnology Inc., Santa Cruz, California, USA) at 1:2,000, rabbit anti-Pbx3 antibody (sc-891 Santa Cruz Santa Cruz Biotechnology Inc., Santa Cruz, California, USA) at 1:1,000, goat anti-ß-galactosidase at 1:10,000 (Arnel Products Co., New York, NY, USA) and mouse anti-Prep1 antibody at 1:200 (05–766 EMD Millipore Inc., Billerica, MA, USA). The pan-Pbx antibody recognizes a common C-terminal peptide in all of the 50 kDa splice variants of Pbx1, Pbx-2 and Pbx3.
Real time PCR
Quantitative PCRs were performed with a Biorad CFX384 system by using preformulated TaqMan Gene expression assays (Invitrogen, Life Technologies Inc., Carlsbad, California, USA) and calculating the results with the comparative Ct method. The assays had the following identification tags: Mm00514509_m1 (DCC), Mm00500896_m1 (netrin-1) and Mm01974474_gH (RPLP0). Dissection of ventral midbrain tissue has been previously described . The dissected ventral midbrains were homogenized, the RNA isolated using the RNeasy Mini kit (Qiagen group, USA) and reverse-transcribed using the VILO Superscript cDNA synthesis kit (Invitrogen, Life Technologies Inc., Carlsbad, California, USA). Each individual PCR was done in three biological replicates.
In silico promoter analysis
Syntenic alignment and analysis of transcription factor binding sites of genomic sequences was performed using ECR Browser and rVista2.0 software (http://www.dcode.org/). For the identification of transcription factor binding sites, rVista2.0 uses a recently developed method, which combines ‘suffix tree’-based fast subsequence search with position weight matrices.
This work was supported by grants from the German Federal Secretary for Education and Research, BMBF Biofutur 98, the University of Trento and the Michael J. Fox Foundation. We thank Licia Selleri for the Pbx1−/− mice, Martyn Goulding for the En1/tauLacZ mice, Kenneth Campbell and Marc Tessier-Lavigne for the Meis and netrin-1 probes. We also thank Gabi Döderlein and Jiawu Feng for technical help. We thank Francesco Blasi and Luis Fernandez-Diaz for providing us with the Prep1 antibody and Danila Baldessari, Federico Cremisi and Vincenzo Vappavigna for review and critical discussion of the manuscript.
- Burglin T: Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. Nucleic Acids Res 1997, 25:4173–4180.PubMedView Article
- Laurent A, Bihan R, Omilli F, Deschamps S, Pellerin I: PBX proteins: much more than Hox cofactors. Int J Dev Biol 2008, 52:9–20.PubMedView Article
- Lufkin T: Transcriptional control of Hox genes in the vertebrate nervous system. Curr Opin Genet Dev 1996, 6:575–580.PubMedView Article
- Gemel J, Jacobsen C, MacArthur CA: Fibroblast growth factor-8 expression is regulated by intronic engrailed and Pbx1-binding sites. J Biol Chem 1999, 274:6020–6026.PubMedView Article
- Peifer M, Wieschaus E: Mutations in the Drosophila gene extradenticle affect the way specific homeo domain proteins regulate segmental identity. Genes Dev 1990, 4:1209–1223.PubMedView Article
- Moens CB, Selleri L: Hox cofactors in vertebrate development. Dev Biol 2006, 291:193–206.PubMedView Article
- Selleri L, Depew MJ, Jacobs Y, Chanda SK, Tsang KY, Cheah KS, Rubenstein JL, O’Gorman S, Cleary ML: Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. Development 2001, 128:3543–3557.PubMed
- Kim SK, Selleri L, Lee JS, Zhang AY, Gu X, Jacobs Y, Cleary ML: Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus. Nat Genet 2002, 30:430–435.PubMedView Article
- Schnabel C, Selleri L, Cleary M: Pbx1 is essential for adrenal development and urogenital differentiation. Genesis 2003, 37:123–130.PubMedView Article
- Schnabel C, Godin R, Cleary M: Pbx1 regulates nephrogenesis and ureteric branching in the developing kidney. Dev Biol 2003, 254:262–276.PubMedView Article
- Manley NR, Selleri L, Brendolan A, Gordon J, Cleary ML: Abnormalities of caudal pharyngeal pouch development in Pbx1 knockout mice mimic loss of Hox3 paralogs. Dev Biol 2004, 276:301–312.PubMedView Article
- Brendolan A, Ferretti E, Salsi V, Moses K, Quaggin S, Blasi F, Cleary ML, Selleri L: A Pbx1-dependent genetic and transcriptional network regulates spleen ontogeny. Development 2005, 132:3113–3126.PubMedView Article
- DiMartino J, Selleri L, Traver D, Firpo M, Rhee J, Warnke R, O’Gorman S, Weissman I, Cleary M: The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver. Blood 2001, 98:618–626.PubMedView Article
- Sgadò P, Albéri L, Gherbassi D, Galasso SL, Ramakers GMJ, Alavian KN, Smidt MP, Dyck RH, Simon HH: Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice. Proc Natl Acad Sci USA 2006, 103:15242–15247.PubMedView Article
- Albéri L, Sgadò P, Simon HH: Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons. Development 2004, 131:3229–3236.PubMedView Article
- Davis CA, Joyner AL: Expression patterns of the homeo box-containing genes En-1 and En-2 and the proto-oncogene int-1 diverge during mouse development. Genes Dev 1988, 2:1736–1744.PubMedView Article
- Joyner AL, Herrup K, Auerbach BA, Davis CA, Rossant J: Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homeobox. Science 1991, 251:1239–1243.PubMedView Article
- Gosgnach S, Lanuza GM, Butt SJB, Saueressig H, Zhang Y, Velasquez T, Riethmacher D, Callaway EM, Kiehn O, Goulding M: V1 spinal neurons regulate the speed of vertebrate locomotor outputs. Nature 2006, 440:215–219.PubMedView Article
- Liu A, Joyner AL: EN and GBX2 play essential roles downstream of FGF8 in patterning the mouse mid/hindbrain region. Development 2001, 128:181–191.PubMed
- Alavian KN, Scholz C, Simon HH: Transcriptional regulation of mesencephalic dopaminergic neurons: the full circle of life and death. Mov Disord 2008, 23:319–328.PubMedView Article
- Erickson T, Scholpp S, Brand M, Moens CB, Waskiewicz AJ: Pbx proteins cooperate with Engrailed to pattern the midbrain-hindbrain and diencephalic-mesencephalic boundaries. Dev Biol 2007, 301:504–517.PubMedView Article
- Wagner K, Mincheva A, Korn B, Lichter P, Popperl H: Pbx4, a new Pbx family member on mouse chromosome 8, is expressed during spermatogenesis. Mech Dev 2001, 103:127–131.PubMedView Article
- Saueressig H, Burrill J, Goulding M: Engrailed-1 and netrin-1 regulate axon pathfinding by association interneurons that project to motor neurons. Development 1999, 126:4201–4212.PubMed
- Capdevila J, Tsukui T, Rodriquez Esteban C, Zappavigna V, Izpisua Belmonte JC: Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by Gremlin. Mol Cell 1999, 4:839–849.PubMedView Article
- Gonzalez-Crespo S, Morata G: Genetic evidence for the subdivision of the arthropod limb into coxopodite and telopodite. Development 1996, 122:3921–3928.PubMed
- Morata G: How Drosophila appendages develop. Nat Rev Mol Cell Biol 2001, 2:89–97.PubMedView Article
- Ryoo HD, Marty T, Casares F, Affolter M, Mann RS: Regulation of Hox target genes by a DNA bound Homothorax/Hox/Extradenticle complex. Development 1999, 126:5137–5148.PubMed
- Abu-Shaar M, Ryoo H, Mann R: Control of the nuclear localization of Extradenticle by competing nuclear import and export signals. Genes Dev 1999, 13:935–945.PubMedView Article
- Berthelsen J, Kilstrup-Nielsen C, Blasi F, Mavilio F, Zappavigna V: The subcellular localization of PBX1 and EXD proteins depends on nuclear import and export signals and is modulated by association with PREP1 and HTH. Genes Dev 1999, 13:946–953.PubMedView Article
- Mercader N, Leonardo E, Azpiazu N, Serrano A, Morata G, Martinez C, Torres M: Conserved regulation of proximodistal limb axis development by Meis1/Hth. Nature 1999, 402:425–429.PubMedView Article
- Jaw TJ, You LR, Knoepfler PS, Yao LC, Pai CY, Tang CY, Chang LP, Berthelsen J, Blasi F, Kamps MP, Sun YH: Direct interaction of two homeoproteins, homothorax and extradenticle, is essential for EXD nuclear localization and function. Mech Dev 2000, 91:279–291.PubMedView Article
- Kilstrup-Nielsen C, Alessio M, Zappavigna V: PBX1 nuclear export is regulated independently of PBX-MEINOX interaction by PKA phosphorylation of the PBC-B domain. EMBO J 2003, 22:89–99.PubMedView Article
- Toresson H, Parmar M, Campbell K: Expression of Meis and Pbx genes and their protein products in the developing telencephalon: implications for regional differentiation. Mech Dev 2000, 94:183–187.PubMedView Article
- Hu Z, Cooper M, Crockett D, Zhou R: Differentiation of the midbrain dopaminergic pathways during mouse development. J Comp Neurol 2004, 476:301–311.PubMedView Article
- Lin L, Rao Y, Isacson O: Netrin-1 and slit-2 regulate and direct neurite growth of ventral midbrain dopaminergic neurons. Mol Cell Neurosci 2005, 28:547–555.PubMedView Article
- Xu B, Goldman JS, Rymar VV, Forget C, Lo PS, Bull SJ, Vereker E, Barker PA, Trudeau LE, Sadikot AF, Kennedy TE: Critical roles for the netrin receptor deleted in colorectal cancer in dopaminergic neuronal precursor migration, axon guidance, and axon arborization. Neuroscience 2010, 169:932–949.PubMedView Article
- Kennedy TE: Cellular mechanisms of netrin function: long-range and short-range actions. Biochem Cell Biol 2000, 78:569–575.PubMedView Article
- Livesey FJ, Hunt SP: Netrin and netrin receptor expression in the embryonic mammalian nervous system suggests roles in retinal, striatal, nigral, and cerebellar development. Mol Cell Neurosci 1997, 8:417–429.PubMedView Article
- Zetterstrom RH, Williams R, Perlmann T, Olson L: Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. Brain Res Mol Brain Res 1996, 41:111–120.PubMedView Article
- Simon HH, Saueressig H, Wurst W, Goulding MD, O’Leary DD: Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J Neurosci 2001, 21:3126–3134.PubMed
- Smidt M, Asbreuk C, Cox J, Chen H, Johnson R, Burbach J: A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat Neurosci 2000, 3:337–341.PubMedView Article
- Smidt M, Van Schaick H, Lanctot C, Tremblay J, Cox J, Van DKA, Wolterink G, Drouin J, Burbach J: A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc Natl Acad Sci U S A 1997, 94:13305–13310.PubMedView Article
- Nosrat C, Tomac A, Hoffer B, Olson L: Cellular and developmental patterns of expression of Ret and glial cell line-derived neurotrophic factor receptor alpha mRNAs. Exp Brain Res 1997, 115:410–422.PubMedView Article
- McCaffery P, Drager UC: High levels of a retinoic acid-generating dehydrogenase in the meso-telencephalic dopamine system. Proc Natl Acad Sci U S A 1994, 91:7772–7776.PubMedView Article
- Rhee JW, Arata A, Selleri L, Jacobs Y, Arata S, Onimaru H, Cleary ML: Pbx3 deficiency results in central hypoventilation. Am J Pathol 2004, 165:1343–1350.PubMedView Article
- Selleri L, DiMartino J, van Deursen J, Brendolan A, Sanyal M, Boon E, Capellini T, Smith KS, Rhee J, Pöpperl H, Grosveld G, Cleary ML: The TALE homeodomain protein Pbx2 is not essential for development and long-term survival. Mol Cell Biol 2004, 24:5324–5331.PubMedView Article
- Roberts V, van Dijk M, Murre C: Localization of Pbx1 transcripts in developing rat embryos. Mech Dev 1995, 51:193–198.PubMedView Article
- Bagri A, Marín O, Plump AS, Mak J, Pleasure SJ, Rubenstein JLR, Tessier-Lavigne M: Slit proteins prevent midline crossing and determine the dorsoventral position of major axonal pathways in the mammalian forebrain. Neuron 2002, 33:233–248.PubMedView Article
- Dugan JP, Stratton A, Riley HP, Farmer WT, Mastick GS: Midbrain dopaminergic axons are guided longitudinally through the diencephalon by Slit/Robo signals. Mol Cell Neurosci 2011, 46:347–356.PubMedView Article
- Comoletti D, De Jaco A, Jennings LL, Flynn RE, Gaietta G, Tsigelny I, Ellisman MH, Taylor P: The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci 2004, 24:4889–4893.PubMedView Article
- Hammond R, Blaess S, Abeliovich A: Sonic hedgehog is a chemoattractant for midbrain dopaminergic axons. PLoS One 2009, 4:e7007.PubMedView Article
- Kolk SM, Gunput R-AF, Tran TS, van den Heuvel DMA, Prasad AA, Hellemons AJCGM, Adolfs Y, Ginty DD, Kolodkin AL, Burbach JPH, Smidt MP, Pasterkamp RJ: Semaphorin 3 F is a bifunctional guidance cue for dopaminergic axons and controls their fasciculation, channeling, rostral growth, and intracortical targeting. J Neurosci 2009, 29:12542–12557.PubMedView Article
- Vives J, Sasajala P, Chang KH, Zhao S, Li M: A mouse model for tracking nigrostriatal dopamine neuron axon growth. Genesis 2008, 46:125–131.PubMedView Article
- Stein E, Tessier-Lavigne M: Hierarchical organization of guidance receptors: silencing of netrin attraction by slit through a Robo/DCC receptor complex. Science 2001, 291:1928–1938.PubMedView Article
- Lesnick TG, Papapetropoulos S, Mash DC, Ffrench-Mullen J, Shehadeh L, de Andrade M, Henley JR, Rocca WA, Ahlskog JE, Maraganore DM: A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. PLoS Genet 2007, 3:e98.PubMedView Article
- Lin L, Lesnick TG, Maraganore DM, Isacson O: Axon guidance and synaptic maintenance: preclinical markers for neurodegenerative disease and therapeutics. Trends Neurosci 2009, 32:142–149.PubMedView Article