Logo of transbhomepageaboutsubmitalertseditorial board
Philos Trans R Soc Lond B Biol Sci. 2001 Oct 29; 356(1414): 1533–1544.
PMCID: PMC1088534

Developmental genetic evidence for a monophyletic origin of the bilaterian brain.


The widely held notion of an independent evolutionary origin of invertebrate and vertebrate brains is based on classical phylogenetic, neuroanatomical and embryological data. The interpretation of these data in favour of a polyphyletic origin of animals brains is currently being challenged by three fundamental findings that derive from comparative molecular, genetic and developmental analyses. First, modern molecular systematics indicates that none of the extant animals correspond to evolutionary intermediates between the protostomes and the deuterostomes, thus making it impossible to deduce the morphological organization of the ancestral bilaterian or its brain from living species. Second, recent molecular genetic evidence for the body axis inversion hypothesis now supports the idea that the basic body plan of vertebrates and invertebrates is similar but inverted, suggesting that the ventral nerve chord of protostome invertebrates is homologous to the dorsal nerve cord of deuterostome chordates. Third, a developmental genetic analysis of the molecular control elements involved in early embryonic brain patterning is uncovering the existence of structurally and functionally homologous genes that have comparable and interchangeable functions in key aspects of brain development in invertebrate and vertebrate model systems. All three of these findings are compatible with the hypothesis of a monophyletic origin of the bilaterian brain. Here we review these findings and consider their significance and implications for current thinking on the evolutionary origin of bilaterian brains. We also preview the impact of comparative functional genomic analyses on our understanding of brain evolution.

Full Text

The Full Text of this article is available as a PDF (1.4M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Acampora D, Mazan S, Lallemand Y, Avantaggiato V, Maury M, Simeone A, Brûlet P. Forebrain and midbrain regions are deleted in Otx2-/- mutants due to a defective anterior neuroectoderm specification during gastrulation. Development. 1995 Oct;121(10):3279–3290. [PubMed]
  • Acampora D, Mazan S, Avantaggiato V, Barone P, Tuorto F, Lallemand Y, Brûlet P, Simeone A. Epilepsy and brain abnormalities in mice lacking the Otx1 gene. Nat Genet. 1996 Oct;14(2):218–222. [PubMed]
  • Acampora D, Avantaggiato V, Tuorto F, Barone P, Reichert H, Finkelstein R, Simeone A. Murine Otx1 and Drosophila otd genes share conserved genetic functions required in invertebrate and vertebrate brain development. Development. 1998 May;125(9):1691–1702. [PubMed]
  • Adoutte A, Balavoine G, Lartillot N, de Rosa R. Animal evolution. The end of the intermediate taxa? Trends Genet. 1999 Mar;15(3):104–108. [PubMed]
  • Adoutte A, Balavoine G, Lartillot N, Lespinet O, Prud'homme B, de Rosa R. The new animal phylogeny: reliability and implications. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4453–4456. [PMC free article] [PubMed]
  • Aguinaldo AM, Turbeville JM, Linford LS, Rivera MC, Garey JR, Raff RA, Lake JA. Evidence for a clade of nematodes, arthropods and other moulting animals. Nature. 1997 May 29;387(6632):489–493. [PubMed]
  • Ang SL, Jin O, Rhinn M, Daigle N, Stevenson L, Rossant J. A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. Development. 1996 Jan;122(1):243–252. [PubMed]
  • Arendt D, Nübler-Jung K. Comparison of early nerve cord development in insects and vertebrates. Development. 1999 Jun;126(11):2309–2325. [PubMed]
  • Bally-Cuif L, Gulisano M, Broccoli V, Boncinelli E. c-otx2 is expressed in two different phases of gastrulation and is sensitive to retinoic acid treatment in chick embryo. Mech Dev. 1995 Jan;49(1-2):49–63. [PubMed]
  • Bell E, Wingate RJ, Lumsden A. Homeotic transformation of rhombomere identity after localized Hoxb1 misexpression. Science. 1999 Jun 25;284(5423):2168–2171. [PubMed]
  • Briscoe J, Sussel L, Serup P, Hartigan-O'Connor D, Jessell TM, Rubenstein JL, Ericson J. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature. 1999 Apr 15;398(6728):622–627. [PubMed]
  • Callaerts P, Halder G, Gehring WJ. PAX-6 in development and evolution. Annu Rev Neurosci. 1997;20:483–532. [PubMed]
  • Chan YM, Jan YN. Conservation of neurogenic genes and mechanisms. Curr Opin Neurobiol. 1999 Oct;9(5):582–588. [PubMed]
  • Chu H, Parras C, White K, Jiménez F. Formation and specification of ventral neuroblasts is controlled by vnd in Drosophila neurogenesis. Genes Dev. 1998 Nov 15;12(22):3613–3624. [PMC free article] [PubMed]
  • Cohen SM, Jürgens G. Mediation of Drosophila head development by gap-like segmentation genes. Nature. 1990 Aug 2;346(6283):482–485. [PubMed]
  • Cornell RA, Ohlen TV. Vnd/nkx, ind/gsh, and msh/msx: conserved regulators of dorsoventral neural patterning? Curr Opin Neurobiol. 2000 Feb;10(1):63–71. [PubMed]
  • De Robertis EM, Sasai Y. A common plan for dorsoventral patterning in Bilateria. Nature. 1996 Mar 7;380(6569):37–40. [PubMed]
  • de Rosa R, Grenier JK, Andreeva T, Cook CE, Adoutte A, Akam M, Carroll SB, Balavoine G. Hox genes in brachiopods and priapulids and protostome evolution. Nature. 1999 Jun 24;399(6738):772–776. [PubMed]
  • Gavalas A, Studer M, Lumsden A, Rijli FM, Krumlauf R, Chambon P. Hoxa1 and Hoxb1 synergize in patterning the hindbrain, cranial nerves and second pharyngeal arch. Development. 1998 Mar;125(6):1123–1136. [PubMed]
  • Gellon G, McGinnis W. Shaping animal body plans in development and evolution by modulation of Hox expression patterns. Bioessays. 1998 Feb;20(2):116–125. [PubMed]
  • Gionti M, Ristoratore F, Di Gregorio A, Aniello F, Branno M, Di Lauro R. Cihox5, a new Ciona intestinalis Hox-related gene, is involved in regionalization of the spinal cord. Dev Genes Evol. 1998 Feb;207(8):515–523. [PubMed]
  • Graham A. Animal phylogeny: root and branch surgery. Curr Biol. 2000 Jan 13;10(1):R36–R38. [PubMed]
  • Halanych KM, Bacheller JD, Aguinaldo AM, Liva SM, Hillis DM, Lake JA. Evidence from 18S ribosomal DNA that the lophophorates are protostome animals. Science. 1995 Mar 17;267(5204):1641–1643. [PubMed]
  • Hanks MC, Loomis CA, Harris E, Tong CX, Anson-Cartwright L, Auerbach A, Joyner A. Drosophila engrailed can substitute for mouse Engrailed1 function in mid-hindbrain, but not limb development. Development. 1998 Nov;125(22):4521–4530. [PubMed]
  • Hartmann B, Reichert H. The genetics of embryonic brain development in Drosophila. Mol Cell Neurosci. 1998 Nov;12(4-5):194–205. [PubMed]
  • Hartmann B, Hirth F, Walldorf U, Reichert H. Expression, regulation and function of the homeobox gene empty spiracles in brain and ventral nerve cord development of Drosophila. Mech Dev. 2000 Feb;90(2):143–153. [PubMed]
  • Hirth F, Reichert H. Conserved genetic programs in insect and mammalian brain development. Bioessays. 1999 Aug;21(8):677–684. [PubMed]
  • Hirth F, Hartmann B, Reichert H. Homeotic gene action in embryonic brain development of Drosophila. Development. 1998 May;125(9):1579–1589. [PubMed]
  • Holland PW, Garcia-Fernàndez J. Hox genes and chordate evolution. Dev Biol. 1996 Feb 1;173(2):382–395. [PubMed]
  • Holley SA, Jackson PD, Sasai Y, Lu B, De Robertis EM, Hoffmann FM, Ferguson EL. A conserved system for dorsal-ventral patterning in insects and vertebrates involving sog and chordin. Nature. 1995 Jul 20;376(6537):249–253. [PubMed]
  • Jungbluth S, Bell E, Lumsden A. Specification of distinct motor neuron identities by the singular activities of individual Hox genes. Development. 1999 Jun;126(12):2751–2758. [PubMed]
  • Katsuyama Y, Wada S, Yasugi S, Saiga H. Expression of the labial group Hox gene HrHox-1 and its alteration induced by retinoic acid in development of the ascidian Halocynthia roretzi. Development. 1995 Oct;121(10):3197–3205. [PubMed]
  • Kaufman TC, Seeger MA, Olsen G. Molecular and genetic organization of the antennapedia gene complex of Drosophila melanogaster. Adv Genet. 1990;27:309–362. [PubMed]
  • Knoll AH, Carroll SB. Early animal evolution: emerging views from comparative biology and geology. Science. 1999 Jun 25;284(5423):2129–2137. [PubMed]
  • Lee JE. Basic helix-loop-helix genes in neural development. Curr Opin Neurobiol. 1997 Feb;7(1):13–20. [PubMed]
  • Leemans R, Egger B, Loop T, Kammermeier L, He H, Hartmann B, Certa U, Hirth F, Reichert H. Quantitative transcript imaging in normal and heat-shocked Drosophila embryos by using high-density oligonucleotide arrays. Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12138–12143. [PMC free article] [PubMed]
  • Leuzinger S, Hirth F, Gerlich D, Acampora D, Simeone A, Gehring WJ, Finkelstein R, Furukubo-Tokunaga K, Reichert H. Equivalence of the fly orthodenticle gene and the human OTX genes in embryonic brain development of Drosophila. Development. 1998 May;125(9):1703–1710. [PubMed]
  • Lewis EB. A gene complex controlling segmentation in Drosophila. Nature. 1978 Dec 7;276(5688):565–570. [PubMed]
  • Li Y, Allende ML, Finkelstein R, Weinberg ES. Expression of two zebrafish orthodenticle-related genes in the embryonic brain. Mech Dev. 1994 Dec;48(3):229–244. [PubMed]
  • Lumsden A, Krumlauf R. Patterning the vertebrate neuraxis. Science. 1996 Nov 15;274(5290):1109–1115. [PubMed]
  • McDonald JA, Holbrook S, Isshiki T, Weiss J, Doe CQ, Mellerick DM. Dorsoventral patterning in the Drosophila central nervous system: the vnd homeobox gene specifies ventral column identity. Genes Dev. 1998 Nov 15;12(22):3603–3612. [PMC free article] [PubMed]
  • McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell. 1992 Jan 24;68(2):283–302. [PubMed]
  • Matsuo I, Kuratani S, Kimura C, Takeda N, Aizawa S. Mouse Otx2 functions in the formation and patterning of rostral head. Genes Dev. 1995 Nov 1;9(21):2646–2658. [PubMed]
  • Mercier P, Simeone A, Cotelli F, Boncinelli E. Expression pattern of two otx genes suggests a role in specifying anterior body structures in zebrafish. Int J Dev Biol. 1995 Aug;39(4):559–573. [PubMed]
  • Nagao T, Leuzinger S, Acampora D, Simeone A, Finkelstein R, Reichert H, Furukubo-Tokunaga K. Developmental rescue of Drosophila cephalic defects by the human Otx genes. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3737–3742. [PMC free article] [PubMed]
  • Oelgeschläger M, Larraín J, Geissert D, De Robertis EM. The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signalling. Nature. 2000 Jun 15;405(6788):757–763. [PMC free article] [PubMed]
  • Pannese M, Polo C, Andreazzoli M, Vignali R, Kablar B, Barsacchi G, Boncinelli E. The Xenopus homologue of Otx2 is a maternal homeobox gene that demarcates and specifies anterior body regions. Development. 1995 Mar;121(3):707–720. [PubMed]
  • Pellegrini M, Mansouri A, Simeone A, Boncinelli E, Gruss P. Dentate gyrus formation requires Emx2. Development. 1996 Dec;122(12):3893–3898. [PubMed]
  • Qiu M, Anderson S, Chen S, Meneses JJ, Hevner R, Kuwana E, Pedersen RA, Rubenstein JL. Mutation of the Emx-1 homeobox gene disrupts the corpus callosum. Dev Biol. 1996 Aug 25;178(1):174–178. [PubMed]
  • Reichert H, Boyan G. Building a brain: developmental insights in insects. Trends Neurosci. 1997 Jun;20(6):258–264. [PubMed]
  • Reichert H, Simeone A. Conserved usage of gap and homeotic genes in patterning the CNS. Curr Opin Neurobiol. 1999 Oct;9(5):589–595. [PubMed]
  • Rubin GM, Yandell MD, Wortman JR, Gabor Miklos GL, Nelson CR, Hariharan IK, Fortini ME, Li PW, Apweiler R, Fleischmann W, et al. Comparative genomics of the eukaryotes. Science. 2000 Mar 24;287(5461):2204–2215. [PMC free article] [PubMed]
  • Sasai Y, De Robertis EM. Ectodermal patterning in vertebrate embryos. Dev Biol. 1997 Feb 1;182(1):5–20. [PubMed]
  • Scott MP. Development: the natural history of genes. Cell. 2000 Jan 7;100(1):27–40. [PubMed]
  • Simeone A. Otx1 and Otx2 in the development and evolution of the mammalian brain. EMBO J. 1998 Dec 1;17(23):6790–6798. [PMC free article] [PubMed]
  • Simeone A, Acampora D, Gulisano M, Stornaiuolo A, Boncinelli E. Nested expression domains of four homeobox genes in developing rostral brain. Nature. 1992 Aug 20;358(6388):687–690. [PubMed]
  • Studer M, Gavalas A, Marshall H, Ariza-McNaughton L, Rijli FM, Chambon P, Krumlauf R. Genetic interactions between Hoxa1 and Hoxb1 reveal new roles in regulation of early hindbrain patterning. Development. 1998 Mar;125(6):1025–1036. [PubMed]
  • Ueki T, Kuratani S, Hirano S, Aizawa S. Otx cognates in a lamprey, Lampetra japonica. Dev Genes Evol. 1998 Jun;208(4):223–228. [PubMed]
  • Umesono Y, Watanabe K, Agata K. Distinct structural domains in the planarian brain defined by the expression of evolutionarily conserved homeobox genes. Dev Genes Evol. 1999 Jan;209(1):31–39. [PubMed]
  • Wada H, Satoh N. Details of the evolutionary history from invertebrates to vertebrates, as deduced from the sequences of 18S rDNA. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1801–1804. [PMC free article] [PubMed]
  • Wada S, Katsuyama Y, Sato Y, Itoh C, Saiga H. Hroth an orthodenticle-related homeobox gene of the ascidian, Halocynthia roretzi: its expression and putative roles in the axis formation during embryogenesis. Mech Dev. 1996 Nov;60(1):59–71. [PubMed]
  • Weiss JB, Von Ohlen T, Mellerick DM, Dressler G, Doe CQ, Scott MP. Dorsoventral patterning in the Drosophila central nervous system: the intermediate neuroblasts defective homeobox gene specifies intermediate column identity. Genes Dev. 1998 Nov 15;12(22):3591–3602. [PMC free article] [PubMed]
  • Williams NA, Holland PW. Gene and domain duplication in the chordate Otx gene family: insights from amphioxus Otx. Mol Biol Evol. 1998 May;15(5):600–607. [PubMed]
  • Yoshida M, Suda Y, Matsuo I, Miyamoto N, Takeda N, Kuratani S, Aizawa S. Emx1 and Emx2 functions in development of dorsal telencephalon. Development. 1997 Jan;124(1):101–111. [PubMed]
  • Younossi-Hartenstein A, Nassif C, Green P, Hartenstein V. Early neurogenesis of the Drosophila brain. J Comp Neurol. 1996 Jul 1;370(3):313–329. [PubMed]
  • Younossi-Hartenstein A, Green P, Liaw GJ, Rudolph K, Lengyel J, Hartenstein V. Control of early neurogenesis of the Drosophila brain by the head gap genes tll, otd, ems, and btd. Dev Biol. 1997 Feb 15;182(2):270–283. [PubMed]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...