Vertebrate Embryo: Neural Patterning


Neural patterning is the process of providing regional identities in neural cells in accordance with their location in the neural tube. Allocation of regional identities is prerequiscent for the following processes of neuronal circuit formation. The neural tube is longitudinal among the body axis thus having anterior–posterior polarity (rostral–caudal in aves, future superior–inferior in adult human). It also has dorsal–ventral polarity and right and left sides. Neural patterning commences as the neural induction takes place progressively in the anterior to posterior direction. By signalling and tissue interaction, the neural tube is divided into the forebrain, midbrain, hindbrain and the spinal cord along the anterior–posterior axis. Further divisions follow to produce differentiation of functional compartments that are defined by the combinatorial expression of molecular markers. The same principle, the initial subdivision by signalling followed by refined compartmentalisation, applies to the acquisition of dorsal–ventral specification as well.

Key Concept

  • Depending on the actual position in the body, cells are specified with respect to the position (positional specification), thus positional identity is acquired. Cells then interpret their positions to differentiate accordingly, thus spatial patterns are formed (see Wolpert, 2011).
  • Neural patterning is the process through which neural progenitors acquire positional identities. The initial allocation of positional information is governed by signalling mechanisms. This is followed by expression of transcription factors, such as Hox genes for the anterior–posterior axis.

Keywords: anterior–posterior; Hox genes; retinoids; fibroblast growth factors; Wnt; dorsal–ventral; BMP (bone morphogenetic protein); Shh (sonic hedgehog)

Figure 1. A–P patterning of the CNS. The scheme is based on chick development. D, dorsal; V, ventral. The first 4–5 somites, called occipital somites, are incorporated into head structures.
Figure 2. Examples of Hox expression in chick embryos revealed by in situ hybridisation with ribonucleic acid (RNA) probes. (a) Hoxb1; (b) Hoxb4; (c) Hoxb9. Arrows indicate anterior‐most boundary of expression in the neural tube: (a) at rhombomere 4, (b) at rhombomere 6/7 boundary, in (c) the somite level 12–13. Most Hox genes show continuous expression in the neural tube and in somites, the latter of which is at more posterior levels. With regard to Hoxb1, the expression is initially seen posterior to rhombomere 4 (inclusive) at early stages; however, the expression domain in the neural tube is split into two: one restricted to rhombomere 4 and another posterior to rhombomere 6/7 boundary, as seen in (a).


Amirthalingam GS, Howard S, Alvarez S, de Lera AR and Itasaki N (2009) Regulation of Hoxb4 induction after neurulation by somite signal and neural competence. BMC Developmental Biology 9: 17.

Balkan W, Colbert M, Bock C and Linney E (1992) Transgenic indicator mice for studying activated retinoic acid receptors during development. PNAS 89: 3347–3351.

Beddington RS and Robertson EJ (1999) Axis development and early asymmetry in mammals. Cell 96: 195–209.

Briscoe J and Ericson J (1999) The specification of neuronal identity by graded Sonic Hedgehog signalling. Seminars in Cell Developmental Biology 10: 353–362.

Concha ML, Burdine RD, Russell C, Schier AF and Wilson SW (2000) A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain. Neuron 28: 399–409.

Delfino‐Machin M, Lunn JS, Breitkreuz DN, Akai J and Storey KG (2005) Specification and maintenance of the spinal cord stem zone. Development 132: 4273–4283.

Diez del Corral R and Storey KG (2004) Opposing FGF and retinoid pathways: a signalling switch that controls differentiation and patterning onset in the extending vertebrate body axis. Bioessays 26: 857–869.

Dupe V and Lumsden A (2001) Hindbrain patterning involves graded responses to retinoic acid signalling. Development 128: 2199–2208.

Durston AJ, Timmermans JP, Hage WJ, et al. (1989) Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature 340: 140–144.

Friling S, Andersson E, Thompson LH, et al. (2009) Efficient production of mesencephalic dopamine neurons by Lmx1a expression in embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America 106: 7613–7618.

Galceran J, Farinas I, Depew MJ, Cleves H and Grosschedl R (1999) Wnt3a−/− ‐like phenotype and limb deficiency in Lef1(−/−)Tcfl(−/−) mice. Genes and Development 13: 709–717.

Gould A, Morrison A, Sproat G et al. (1997) Positive cross‐regulation and enhancer sharing: two mechanisms for specifying overlapping Hox expression patterns. Genes Development 11: 900–913

Gould A, Itasaki N and Krumlauf R (1998) Initiation of rhombomeric Hoxb4 expression requires induction by somites and a retinoid pathway. Neuron 21: 39–51.

Hashiguchi M and Mullins MC (2013) Anteroposterior and dorsoventral patterning are coordinated by an identical patterning clock. Development 140: 1970–1980.

Irioka T, Watanabe K, Mizusawa H, Mizuseki K and Sasai Y (2005) Distinct effects of caudalizing factors on regional specification of embryonic stem cell‐derived neural precursors. Brain research Developmental brain research 154: 63–70.

Itasaki N, Sharpe J, Morrison A and Krumlauf R (1996) Reprogramming Hox expression in the vertebrate hindbrain: influence of paraxial mesoderm and rhombomere transposition. Neuron 16: 487–500.

Joyner AL, Liu A and Millet S (2000) Otx2, Gbx2 and Fgf8 interact to position and maintain a mid‐hindbrain organizer. Current Opinion in Cell Biology 12: 736–741.

Kawasaki H, Mizuseki K, Nishikawa S, et al. (2000) Induction of midbrain dopaminergic neurons from ES cells by stromal cell‐derived inducing activity. Neuron 28: 31–40.

Kiecker C and Niehrs C (2001a) The role of prechordal mesoderm in neural patterning. Current Opinion in Neurobiology 11: 27–33.

Kiecker C and Niehrs C (2001b) A morphogen gradient of Wnt/beta‐catenin signalling regulates anteroposterior neural patterning in Xenopus. Development 128: 4189–4201.

Kirkeby A, Grealish S, Wolf DA, et al. (2012) Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep 1: 703–714.

Kim CH, Oda T, Itoh M, et al. (2000) Repressor activity of Headless/Tcf3 is essential for vertebrate head formation. Nature 407: 913–916.

Kondo T and Duboule D (1999) Breaking colinearity in the mouse HoxD complex. Cell 97: 407–417.

Lekven AC, Thorpe CJ, Waxman JS and Moon RT (2001) Zebrafish wnt8 encodes two wnt8 proteins on a bicistronic transcript and is required for mesoderm and neuroectoderm patterning. Developmental Cell 1: 103–114.

Liang JO, Etheridge A, Hantsoo L, et al. (2000) Asymmetric Nodal signalling in the Zebrafish diencephalon positions the pineal organ. Development 127: 5101–5112.

Lickert H, Domon C, Huls G, et al. (2000) Wnt/β‐catenin signaling regulates the expression of the homeobox gene Cdx1 in embryonic intestine. Development 127: 3805–3813.

Maden M, Gale E, Kostetskii I and Zile M (1996) Vitamin A‐deficient quail embryos have half a hindbrain and other neural defects. Current Biology 6: 417–426.

Maden M, Sonneveld E, van der Saag PT and Gale E (1998) The distribution of endogenous retinoic acid in the chick embryo: implications for the developmental mechanisms. Development 125: 4133–4144.

Mathis L, Kulesa PM and Fraser SE (2001) FGF receptor signalling is required to maintain neural progenitors during Hensen's node progression. Nature Cell Biology 3: 559–566.

Mizuseki K, Sakamoto T, Watanabe K, et al. (2003) Generation of neural crest‐derived peripheral neurons and floor plate cells from mouse and primate embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America 100: 5828–5833.

Niederreither K and Dolle P (2008) Retinoic acid in development: towards an integrated view. Nature Reviews Genetics 9: 541–553.

Niederreither K, Subbarayan V, Dolle P and Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post‐implantation development. Nature Genetics 21: 444–448.

Niehrs C (1999) Head in the WNT. Trends in Genetics 15: 314–319.

Nieuwkoop PD (1952) Activation and organization of the central nervous system in amphibians. Journal of Experimental Zoology 120: 1–106.

Okada Y, Shimazaki T, Sobue G and Okano H (2004) Retinoic‐acid‐concentration‐dependent acquisition of neural cell identity during in vitro differentiation of mouse embryonic stem cells. Developmental biology 275: 124–142.

Pownall ME, Tucker AS, Slack JM and Isaacs HV (1996) eFGF, Xcad3 and Hox genes form a molecular pathway that establishes the anteroposterior axis in Xenopus. Development 122: 3881–3892.

Quinonez SC and Innis JW (2014) Human HOX gene disorders. Molecular Genetics and Metabolism 111: 4–15.

Reijntjes S, Gale E and Maden M (2004) Generating gradients of retinoic acid in the chick embryo:Cyp26C1 expression and a comparative analysis of the Cyp26 enzymes. Developmental Dynamics 230: 509–517.

Rossant J, Zirnigbl R, Cado D, Shago M and Gignere V (1991) Expression of a retinoic acid response element‐hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis. Genes and Development 5: 1333–1344.

Rowan AM, Stern CD and Storey KG (1999) Axial mesendoderm refines rostrocaudal pattern in the chick nervous system. Development 126: 2921–2934.

Saude L, Woolley K, Martin P, Driever W and Stemple DL (2000) Axis‐inducing activities and cell fates of the zebrafish organizer. Development 127: 3407–3417.

Simeone A, Acampora D, Arcioni L, et al. (1990) Sequential activation of human HOX2 homeobox genes by retinoic acid in human embryonal carcinoma cells. Nature 346: 763–766.

Stern CD (2005) Neural induction: old problem, new findings, yet more questions. Development 132: 2007–2021.

Storey KG, Crossley JM, De Robertis EM, Norris WE and Stern CD (1992) Neural induction and regionalisation in the chick embryo. Development 114: 729–741.

Su HL, Muguruma K, Matsuo‐Takasaki M, et al. (2006) Generation of cerebellar neuron precursors from embryonic stem cells. Developmental biology 290: 287–296.

Takada S, Stark KL, Shea MJ, et al. (1994) Wnt‐3a regulates somite and tailbud formation in the mouse embryo. Genes and Development 8: 174–189.

Watanabe K, Kamiya D, Nishiyama A, et al. (2005) Directed differentiation of telencephalic precursors from embryonic stem cells. Nature neuroscience 8: 288–296.

Wataya T, Ando S, Muguruma K, et al. (2008) Minimization of exogenous signals in ES cell culture induces rostral hypothalamic differentiation. Proceedings of the National Academy of Sciences of the United States of America 105: 11796–11801.

Wilkinson DG, Bailes JA and McMahon AP (1987) Expression of the proto-oncogene int‐1 is restricted to specific neural cells in the developing mouse embryo. Cell 50: 79–88.

Wilkinson DG (2001) Multiple roles of EPH receptors and ephrins in neural development. Nature Reviews in Neuroscience 2 (3): 155–164.

Wolpert L (2011) Positional information and patterning revisited. J Theor Biol. 269: 359–365.

Woo K and Fraser SE (1997) Specification of the zebrafish nervous system by nonaxial signals. Science 277: 254–257.

Further Reading

Gilbert SF (2013) Developmental Biology, 10th edn. Chapter 8, Early development in vertebrates: Amphibians and fish; Chapter 9, Early development in vertebrates: Birds and Mammals Boston, MA: Sinauer Associates.

Slack J (2012) Essential Developmental Biology, 3rd edn. Chichester, UK: Wiley‐Blackwell.

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Itasaki, Nobue(Feb 2015) Vertebrate Embryo: Neural Patterning. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000737.pub3]