Advertisement
JOURNAL ARTICLES
Role of Hoxa-2 in axon pathfinding and rostral hindbrain patterning
A. Gavalas, M. Davenne, A. Lumsden, P. Chambon, F.M. Rijli
Development 1997 124: 3693-3702;

Summary

Segmentation plays an important role in neuronal diversification and organisation in the developing hindbrain. For instance, cranial nerve branchiomotor nuclei are organised segmentally within the basal plates of successive pairs of rhombomeres. To reach their targets, motor axons follow highly stereotyped pathways exiting the hindbrain only via specific exit points in the even-numbered rhombomeres. Hox genes are good candidates for controlling this pathfinding, since they are segmentally expressed and involved in rhombomeric patterning. Here we report that in Hoxa-2(−/−) embryos, the segmental identities of rhombomere (r) 2 and r3 are molecularly as well as anatomically altered. Cellular analysis by retrograde dye labelling reveals that r2 and r3 trigeminal motor axons turn caudally and exit the hindbrain from the r4 facial nerve exit point and not from their normal exit point in r2. Furthermore, dorsal r2-r3 patterning is affected, with loss of cochlear nuclei and enlargement of the lateral part of the cerebellum. These results point to a novel role for Hoxa-2 in the control of r2-r3 motor axon guidance, and also suggest that its absence may lead to homeotic changes in the alar plates of these rhombomeres.

REFERENCES

    1. Alder J.,
    2. Cho N. K.,
    3. Hatten M. E.
    (1996) Embryonic precursor cells from the rhombic lip are specified to a cerebellar granule neuron identity. Neuron 17, 389–399
    OpenUrlCrossRefPubMedWeb of Science
    1. Altman J.,
    2. Bayer S.
    (1978) Prenatal development of the cerebellarsystem in the rat. Cytogenesis and histogenesis of the deep nuclei and the cortex of the cerebellum. J. Comp. Neur 179, 23–48
    OpenUrlCrossRefPubMedWeb of Science
    1. Birgbauer E.,
    2. Fraser S. E.
    (1994) Violation of cell lineage restriction compartments in the chick hindbrain. Development 120, 1347–1356
    OpenUrlAbstract
    1. Bockman D. E.,
    2. Kirby M. L.
    (1984) Dependence of thymus development on derivatives of the neural crest. Science 223, 498–500
    OpenUrlAbstract/FREE Full Text
    1. Carpenter E. M.,
    2. Goddard J. M.,
    3. Chisaka O.,
    4. Manley N. R.,
    5. Capecchi M. R.
    (1993) Loss of HoxA-1 (Hox-1. 6) function results in the reorganization of the murine hindbrain. Development 118, 1063–1075
    OpenUrlAbstract/FREE Full Text
    1. Chang S.,
    2. Fan J.,
    3. Nayak J.
    (1992) Pathfinding by cranial nerve VII (facial) motoneurons in the chick hindbrain. Development 114, 815–823
    OpenUrlAbstract
    1. Cheng H. J.,
    2. Nakamoto M.,
    3. Bergemann A. D.,
    4. Flanagan J. G.
    (1995) Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinoectal projection map. Cell 82, 371–381
    OpenUrlCrossRefPubMedWeb of Science
    1. Chisaka O.,
    2. Capecchi M. R.
    (1991) Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene Hox-1. 5. Nature 350, 473–479
    OpenUrlCrossRefPubMed
    1. Chisaka O.,
    2. Musci T. S.,
    3. Capecchi M. R.
    (1992) Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1. 6. Nature 355, 516–520
    OpenUrlCrossRefPubMed
    1. Couly G. F.,
    2. Coltey P. M.,
    3. Le Douarin N.
    (1993) The triple origin of skull in higher vertebrates: a study in quail-chick chimeras. Development 117, 409–429
    OpenUrlAbstract
    1. Davis C. A.,
    2. Joyner A. L.
    (1988) Expression patterns of the homeobox containing genes En-1 and En-2 and the proto-oncogene int-1 diverge during mouse development. Genes Dev 2, 1736–1744
    OpenUrlAbstract/FREE Full Text
    1. Dolle P.,
    2. Lufkin T.,
    3. Krumlauf R.,
    4. Mark M.,
    5. Duboule D.,
    6. Chambon P.
    (1993) Local alterations of Krox-20 and Hox gene expression in the hindbrain suggest lack of rhombomeres 4 and 5 in homozygote null Hoxa-1 (Hox-1. 6) mutant embryos.Proc. Natl. Acad. Sci. USA 90, 7666–7670
    OpenUrlAbstract/FREE Full Text
    1. Drescher U.,
    2. Kremoser C.,
    3. Handwerker C.,
    4. Loschinger J.,
    5. Noda M.,
    6. Bonhoeffer F.
    (1995) In vitro guidance of retinal ganglion cell axons by RAGS, a 25kDa tactal protein related to ligands for Eph receptor tyrosine kinases. Cell 82, 359–370
    OpenUrlCrossRefPubMedWeb of Science
    1. Dupe V.,
    2. Davenne M.,
    3. Brocard J.,
    4. Dolle P.,
    5. Mark M.,
    6. Dierich A.,
    7. Chambon P.,
    8. Rijli F. M.
    (1997) In vivo functional analysis of the Hoxa-1 3retinoic acid response element (3 RARE). Development 124, 399–410
    OpenUrlAbstract
    1. Fraser S.,
    2. Keynes R.,
    3. Lumsden A.
    (1990) Segmentation in the chick embryo hindbrain is defined by cell lineage restrictions. Nature 344, 431–435
    OpenUrlCrossRefPubMed
    1. Frohman M. A.,
    2. Boyle M.,
    3. Martin G. R.
    (1990) Isolation of the mouse Hox-2. 9 gene; analysis of embryonic expression suggests that positional information along the anterior-posterior axis is specified by mesoderm. Development 110, 589–607
    OpenUrlAbstract/FREE Full Text
    1. Gendron-Maguire M.,
    2. Mallo M.,
    3. Zhang M.,
    4. Gridley T.
    (1993) Hoxa-2 mutant mice exhibit homeotic transformation of skeletal elements derived from cranial neural crest. Cell 75, 1317–1331
    OpenUrlCrossRefPubMedWeb of Science
    1. Gilardi-Hebenstreit P.,
    2. Nieto M. A.,
    3. Frain M.,
    4. Mattei M.-G.,
    5. Chestier A.,
    6. Wilkinson D. G.,
    7. Charnay P.
    (1992) An Eph-related receptor protein tyrosine kinase gene segmentally expressed in the developing mouse hindbrain. Oncogene 7, 2499–2506
    OpenUrlPubMedWeb of Science
    1. Goddard J. M.,
    2. Rossel M.,
    3. Manley N. R.,
    4. Capecchi M. R.
    (1996) Mice with targeted disruption of Hoxb-1 fail to form the motor nucleus of the VIIth nerve. Development 122, 3217–3228
    OpenUrlAbstract
    1. Graham A.,
    2. Francis West P.,
    3. Lumsden A.
    (1994) The signalling molecule BMP-4 mediates apoptosis in the rhombencephalic neural crest. Nature 372, 684–686
    OpenUrlCrossRefPubMed
    1. Graham A.,
    2. Heyman I.,
    3. Lumsden A.
    (1993) Even-numbered rhombomeres control the apoptotic elimination of neural crest cells from odd-numbered rhombomeres in in the chick hindbrain. Development 119, 233–245
    OpenUrlAbstract
    1. Guthrie S.,
    2. Lumsden A.
    (1992) Motor neuron pathfinding following rhombomere reversals in the chick embryo hindbrain. Development 114, 663–673
    OpenUrlAbstract
    1. Hallonet M. E. R.,
    2. Le Douarin N. M.
    (1993) Tracing neuroepithelialcells of the mesencephalic and metencephalic alar plates during cerebellar ontogeny in quail-chick chimaeras. Eur. J. Neurosci 5, 1145–1155
    OpenUrlCrossRefPubMedWeb of Science
    1. Hallonet M. E. R.,
    2. Teillet M. A.,
    3. Le Douarin N. M.
    (1990) A new approach to the development of the cerrebelum provided by the quail-chick marker system. Development 108, 19–31
    OpenUrlAbstract
    1. Hatten M. E.,
    2. Heintz N.
    (1995) Mechanisms of neural patterning and specification in the developing cerebellum. Annu. Rev. Neurosci 18, 385–408
    OpenUrlPubMedWeb of Science
    1. Kessel M.
    (1993) Reversal of axonal pathways from rhombomere 3 correlates with extra Hox expression domains. Neuron 10, 379–393
    OpenUrlCrossRefPubMedWeb of Science
    1. Keynes R.,
    2. Krumlauf R.
    (1994) Hox genes and regionalization of the nervous system. Annu. Rev. Neurosci 17, 109–132
    OpenUrlCrossRefPubMedWeb of Science
    1. Köntges G.,
    2. Lumsden A.
    (1996) Rhomboencephalic neural crest segmentation is preserved throughout craniofacial ontogeny. Development 122, 3229–3242
    OpenUrlAbstract
    1. Krumlauf R.
    (1993) Hox genes and pattern formation in the branchial region of the vertebrate head. Trends Genet 9, 106–112
    OpenUrlCrossRefPubMedWeb of Science
    1. Le Lievre C. S.,
    2. Le Douarin N. M.
    (1975) Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos. J. Embryol. Exp. Morph 34, 125–154
    OpenUrlPubMedWeb of Science
    1. Lufkin T.,
    2. Dierich A.,
    3. Le Meur M.,
    4. Mark M.,
    5. Chambon P.
    (1991) Disruption of the Hox-1. 6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell 66, 1105–1119
    OpenUrlCrossRefPubMedWeb of Science
    1. Lumsden A.
    (1990) The cellular basis of segmentation in the developing hindbrain. Trends Neurosci 13, 329–335
    OpenUrlCrossRefPubMedWeb of Science
    1. Lumsden A.,
    2. Keynes R.
    (1989) Segmental patterns of neural development in the chick hindbrain. Nature 337, 424–428
    OpenUrlCrossRefPubMed
    1. Lumsden A.,
    2. Sprawson N.,
    3. Graham A.
    (1991) Segmental origin and migration of neural crest cells in the hindbrain region of the chick embryo. Development 113, 1281–1291
    OpenUrlAbstract
    1. Marin F.,
    2. Puelles L.
    (1995) Morphological fate of rhombomeres in quail/chick chimeras: a segmental analysis of hindbrain nuclei. Eur. J. Neurosci 7, 1714–1738
    OpenUrlCrossRefPubMedWeb of Science
    1. Mark M.,
    2. Lufkin T.,
    3. Vonesch J. L.,
    4. Ruberte E.,
    5. Olivo J. C.,
    6. Gorry P.,
    7. Lumsden A.,
    8. Chambon P.
    (1993) Two rhombomeres are altered in Hoxa-1 mutant mice. Development 119, 319–338
    OpenUrlAbstract
    1. Marshall H.,
    2. Nonchev S.,
    3. Sham M. H.,
    4. Muchamore I.,
    5. Lumsden A.,
    6. Krumlauf R.
    (1992) Retinoic acid alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity. Nature 360, 737–741
    OpenUrlCrossRefPubMed
    1. Martinez S.,
    2. Alvarado-Mallart R. M.
    (1989) Rostral cerebellum originates from the caudal portion of the so-called mesencephalic vesicle: a study using chick/quail chimeras. Eur. J. Neurosci 1, 549–560
    OpenUrlCrossRefPubMedWeb of Science
    1. Martinez S.,
    2. Marin F.,
    3. Nieto M. A.,
    4. Puelles L.
    (1995) Induction of ectopic engrailed expression and fate change in avian rhombomeres: intersegmental boundaries as barriers. Mech. Develop 51, 289–303
    OpenUrlCrossRefPubMedWeb of Science
    1. Millen K. J.,
    2. Wurts W.,
    3. Herrup K.,
    4. Joyner A. L.
    (1994) Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants. Development 120, 695–706
    OpenUrlAbstract
    1. Niederländer C.,
    2. Lumsden A.
    (1996) Late emigrating crest cells migrate specifically to the exit points of cranial branchiomotor nerves. Development 122, 2367–2374
    OpenUrlAbstract
    1. Nieto M. A.,
    2. Gilardi-Hebenstreit P.,
    3. Charnay P.,
    4. Wilkinson D. G.
    (1992) A receptor protein tyrosine kinase implicated in the segmental patterning of the hindbrain and mesoderm. Development 116, 37–50
    OpenUrl
    1. Nonchev S.,
    2. Vesque C.,
    3. Maconochie M.,
    4. Seitanidou T.,
    5. Aiza-McNaughton L.,
    6. Frain M.,
    7. Marshall H.,
    8. Sham M. H.,
    9. Krumlauf R.,
    10. Charnay P.
    (1996) Segmental expression of Hoxa-2 in the hindbrain is directly regulated by Krox-20. Development 122, 543–554
    OpenUrlAbstract
    1. Prince V.,
    2. Lumsden A.
    (1994) Hoxa-2 expression in normal and transposed rhombomeres: independent regulation in the neural tube and neural crest. Development 120, 911–923
    OpenUrlAbstract
    1. Rijli F. M.,
    2. Mark M.,
    3. Lakkaraju S.,
    4. Dierich A.,
    5. Dolle P.,
    6. Chambon P.
    (1993) A homeotic transformation is generated in the rostral branchial region of the head by disruption of Hoxa-2, which acts as a selector gene. Cell 75, 1333–1349
    OpenUrlCrossRefPubMedWeb of Science
    1. Schneider-Maunoury S.,
    2. Seitanidou T.,
    3. Charnay P.,
    4. Lumsden A.
    (1997) Segmental and neuronal architecture of the hindbrain of Krox-20 mouse mutants. Development 124, 1215–1226
    OpenUrlAbstract
    1. Schneider-Maunoury S.,
    2. Topilko P.,
    3. Seitanidou T.,
    4. Levi G.,
    5. Cohen-Tannoudji M.,
    6. Pournin S.,
    7. Babinet C.,
    8. Charnay P.
    (1993) Disruption of Krox-20 results in alteration of rhombomeres 3 and 5 in the developing hindbrain. Cell 75, 1199–1214
    OpenUrlCrossRefPubMedWeb of Science
    1. Schubert F. R.,
    2. Fainsod A.,
    3. Gruenbaum Y.,
    4. Gruss P.
    (1995) Expression of the novel murine homeobox gene Sax-1 in the developing nervous system. Mech. Development 51, 99–114
    OpenUrlCrossRefPubMedWeb of Science
    1. Sechrist J.,
    2. Serbedzija G. N.,
    3. Scherson T.,
    4. Fraser S. E.,
    5. Bronner-Fraser M.
    (1993) Segmental migration of the hindbrain neural crest does not arise from its segmental generation. Development 118, 691–703
    OpenUrlAbstract
    1. Sham M. H.,
    2. Vesque C.,
    3. Nonchev S.,
    4. Marshall H.,
    5. Frain M.,
    6. Gupta R. D.,
    7. Whiting J.,
    8. Wilkinson D.,
    9. Charnay P.,
    10. Krumlauf R.
    (1993) The zinc finger gene Krox20 regulates Hoxb-2 (Hox2. 8) during hindbrain segmentation. Cell 72, 183–196
    OpenUrlCrossRefPubMedWeb of Science
    1. Simeone A.,
    2. Acampora D.,
    3. Guilisano M.,
    4. Stornaiuolo A.,
    5. Boncinelli E.
    (1992) Nested expression domains of four homeobox genes in the developing brain. Nature 358, 687–690
    OpenUrlCrossRefPubMed
    1. Studer M.,
    2. Lumsden A.,
    3. Ariza-McNaughton L.,
    4. Bradley A.,
    5. Krumlauf R.
    (1996) Altered segmental identity and abnormal migration of motor neurons in mice lacking Hoxb-1. Nature 384, 630–634
    OpenUrlCrossRefPubMed
    1. Swiatek P. J.,
    2. Gridley T.
    (1993) Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox-20. Genes Dev 7, 2071–2084
    OpenUrlAbstract/FREE Full Text
    1. Tan K.,
    2. Le Douarin N. M.
    (1991) Development of the nuclei and cell migration in the medulla oblongata-application of the quail-chick chimera system. Anat. Embryol 183, 321–343
    OpenUrlPubMed
    1. Taneja R.,
    2. Thisse B.,
    3. Rijli F. M.,
    4. Thisse C.,
    5. Bouillet P.,
    6. Dolle P.,
    7. Chambon P.
    (1996) The expression pattern of the mouse receptor tyrosinekinase gene MDK1 is conserved through evolution and requires Hoxa-2 for rhombomere-specific expression in mouse embryos. Dev. Biol 177, 397–412
    OpenUrlCrossRefPubMed
    1. Tessier-Lavigne M.,
    2. Goodman C. S.
    (1996) The molecular biology of axon guidance. Science 274, 1123–1133
    OpenUrlAbstract/FREE Full Text
    1. Varela-Echavarria A.,
    2. Guthrie S.
    (1997) Molecules making waves in axon guidance. Genes Dev 11, 545–557
    OpenUrlFREE Full Text
    1. Wang H. U.,
    2. Anderson D. J.
    (1997) Eph family transmembrane ligands can mediate repulsive guidance of trunk neural crest migration and motor axon outgrowth. Neuron 18, 383–396
    OpenUrlCrossRefPubMedWeb of Science
    1. Wilkinson D. G.,
    2. Bhatt S.,
    3. Chavrier P.,
    4. Bravo R.,
    5. Charnay P.
    (1989) Segment-specific expression of a zinc-finger gene in the developing nervous system of the mouse. Nature 337, 461–464
    OpenUrlCrossRefPubMed
    1. Wingate R.,
    2. Lumsden A.
    (1996) Persistence of rhombomeric organisation in in the postsegmental avian hindbrain. Development 122, 2143–2152
    OpenUrlAbstract
    1. Yang X. W.,
    2. Zhong R.,
    3. Heintz N.
    (1996) Granule cell specification in the developing mouse brain as defined by the expression of the zinc finger transcription factor RU49. Development 122, 555–566
    OpenUrlAbstract
    1. Zhang M.,
    2. Kim H. J.,
    3. Marshall H.,
    4. Gendron-Maguire M.,
    5. Lucas D.A.,
    6. Baron A.,
    7. Gudas L. J.,
    8. Gridley T.,
    9. Krumlauf R.,
    10. Grippo J. F.
    (1994) : Ectopic Hoxa-1 induces rhombomere transformation in mouse hindbrain. Development 120, 2431–2442
    OpenUrlAbstract/FREE Full Text
Back to top

 Download PDF

Email
JOURNAL ARTICLES
Role of Hoxa-2 in axon pathfinding and rostral hindbrain patterning
A. Gavalas, M. Davenne, A. Lumsden, P. Chambon, F.M. Rijli
Development 1997 124: 3693-3702;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Alerts

Article navigation

Other journals from The Company of Biologists

Advertisement

Interviews — Bénédicte Sanson and Kate Storey

Bénédicte Sanson and Kate Storey

Hear from Bénédicte Sanson, winner of the BSDB’s Cheryll Tickle medal, and Kate Storey, winner of the BSDB’s Waddington Medal, as they discuss their research, the future of the field and the importance of collaboration.

Review Commons launches

We're excited to be an affiliate journal for Review Commons, the ASAPbio/EMBO platform for high-quality journal-independent peer-review in the life sciences, which went live on 09 December.

Early-career researchers can apply for up to £2,500 to offset the cost of travel and expenses to make collaborative visits to other labs around the world. Read about Peter’s experience in Switzerland, where he joined forces with the Lutolf lab to refine a protocol for producing gastruloids.

Publishing peer review reports

To continue working towards transparency around the editorial process, Development now publishes a ‘Peer review history file’ alongside published papers. Read more about the policy and see the reports for yourself in one the first papers to publish the reports (under the ‘Info & metrics’ tab).

Development at a glance — Cell interactions in collective cell migration

Extract from the poster showing specific cell-cell interactions in metastasis.

Take a look at the latest poster and accompanying article by Denise Montell and her colleagues from the University of California, where they describe a sampling of both known and new cells that migrate collectively in vivo.