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  • Review Article
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Half a century of neural prepatterning: the story of a few bristles and many genes

Nature Reviews Neuroscience volume 4, pages 587–598 (2003)Cite this article

Key Points

  • Almost 50 years ago, Curt Stern asked why the sensory bristles on the Drosophila notum appeared at stereotyped positions. He found that the achaeate (ac) gene permitted bristles to develop only in places where there was a predetermined invisible pattern — the neural prepattern.

  • The genes of the achaete–scute complex (ASC) code for basic helix–loop–helix (bHLH) transcription factors. Their ability to enable cells to become neural precursors gave rise to the generic name 'proneural' factors. Their function is tightly controlled, both spatially and temporally, during development. The ASC contains cis-regulatory elements (enhancers), which drive ac and scute (sc) expression at specific sites.

  • The dorsocentral (DC) enhancer drives ac/sc expression in the proneural cluster that gives rise to two large DC bristles. The transcription factor Pannier (Pnr) seems to be a direct activator of as/sc in the DC cluster, and the Apterous cofactor Chip also seems to participate in the regulation of ac/sc by the DC enhancer. The signalling molecule Decapentaplegic (Dpp) helps to establish and position the DC cluster.

  • The genes araucan, caupolican and mirror — three related homeobox genes of the Iroquois complex (Iro-C) — are constituents of the prepattern that directs ac/sc expression in the lateral proneural clusters of the notum.

  • In the Drosophila embryo, neural prepatterning has been studied mostly in the developing ventral cord. A gradient of the transcription factor Dorsal (Dl) determines the position and extent of the neuroectoderm by activating neural prepattern genes and antagonizing Dpp.

  • In the neuroectoderm, anteroposterior and dorsoventral prepatterning genes make up a checkerboard pattern that defines the position of the proneural clusters. Along the anterior/posterior axis, genes such as wingless, hedgehog, patched and engrailed are expressed in defined rows of cells. Three homeobox genes — ventral nervous system defective, intermediate neuroblasts defective and muscle segment homeobox — establish the basic dorsal/ventral subdivisions.

  • Some of the signalling molecules and prepattern factors that participate in neuronal specification and differentiation are the same in flies and vertebrates. Unlike their Drosophila counterparts, vertebrate proneural genes do not participate in the choice between neural and epidermal fate.

  • In the vertebrate spinal cord, opposing gradients of Sonic Hedgehog, which emanate from the floor plate and notochord, and bone morphogenetic proteins and Wnts, which originate in the roof plate and adjacent nonneural tissue, activate several prepattern factors in partially overlapping domains.

  • The spinal cord is subdivided dorsoventrally into regions that are defined by the expression domains of the homeobox genes Nkx2.2, Nkx6.1, Nkx6.2, Dbx1, Dbx2, Msx1, Pax6, Pax7 and Irx3, and the bHLH gene Olig2. The ventral and dorsal limits of the domains are defined and maintained by mutual repression between pairs of dorsally and ventrally expressed genes.

  • Stern's prepattern concept has been extended, from a collection of genes whose products activate proneural genes, to genes that subdivide a territory and combinatorially promote different neuronal identities.

Abstract

In 1954, Curt Stern proposed the concept of the neural prepattern, meaning the underlying positional information in an undifferentiated epithelium that determined where neural differentiation could take place. Subsequent work gave a molecular basis to this concept, which was equated to a combination of transcription factors deployed in partially overlapping spatial domains that regulated proneural genes and, thereby, neural differentiation. Here, we review the work that, in the past few years, has identified many prepattern genes and has disclosed that their function is not limited to the regulation of proneural genes.

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Figure 1: Genesis of a Drosophila notum macrochaeta.
Figure 2: Prepattern factors and signalling molecules in the notum territory of the third instar wing disc.
Figure 3: Neural patterning along the dorsoventral axis of the Drosophila embryo.
Figure 4: Expression of proneural and dorsoventral prepatterning genes in the vertebrate spinal cord.
Figure 5: Expression of Gli2, Gli3 and Sonic Hedgehog (Shh), and spinal cord progenitor domains, in wild-type and mutant mice.
Figure 6: Expression of anteroposterior prepattern genes in the developing vertebrate nervous system.

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Acknowledgements

We are grateful to J. F. de Celis, R. Diez del Corral, M. Ruiz-Gómez, K. Storey and colleagues of our laboratory for constructive criticism of the manuscript. We apologize to investigators whose work has not been mentioned due to space limitations. Grants from Dirección General de Investigación Científica y Técnica, Comunidad Autónoma de Madrid, and an institutional grant from Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa are acknowledged.

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Authors and Affiliations

  1. Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Cantoblanco, Madrid, 28049, Spain

    José Luis Gómez-Skarmeta, Sonsoles Campuzano & Juan Modolell

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  1. José Luis Gómez-Skarmeta
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  2. Sonsoles Campuzano
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  3. Juan Modolell
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Correspondence to Juan Modolell.

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DATABASES

FlyBase

ac

araucan

asense

BarH1

BarH2

brinker

caupolican

Chip

D

da

Dpp

EGFR

emc

engrailed

gooseberry

Hairy

hedgehog

ind

invected

l'sc

mirror

msh

patched

Pnr

rho

sal

sal-r

sc

short gastrulation

snail

SoxN

Ush

vnd

Wg

LocusLink

Bf1

Cdx1

Dbx1

Dbx2

En1

Fgf8

Gbx2

Gli

Irx3

Mash1

Math1

Msx1

Ngn1

Ngn2

Nkx2.2

Nkx6.1

Nkx6.2

Olig2

Otx2

Pax2

Pax6

Pax7

Shh

Six3

Wnt1

Wnt3a

Glossary

BASIC HELIX–LOOP–HELIX

(bHLH). A structural motif present in many transcription factors that is characterized by two α-helices separated by a loop. The helices mediate dimerization, and the adjacent basic region is required for DNA binding.

GATA TRANSCRIPTION FACTOR

Refers to a family of zinc-finger domain containing factors that recognize the DNA sequence (A/T)GATA(A/G).

WNT PROTEINS

A family of highly conserved secreted signalling molecules that regulate cell–cell interactions during embryogenesis. Wnt proteins bind on the cell surface to receptors of the Frizzled family.

FOG (FRIEND OF GATA) FACTORS

A family of multiple zinc-finger proteins that interact with GATA factors and modulate their activity as transcriptional regulators.

HOMEODOMAIN

A 60-amino-acid DNA-binding domain that comprises three α-helices and is found in many transcription factors.

ZINC-FINGER

A protein module in which cysteine or cysteine–histidine residues coordinate a zinc ion. Zinc-fingers are often used in DNA recognition and in protein–protein interactions.

SOX DOMAIN

A DNA-binding domain of the high mobility group (HMG) class, which is closely related to the DNA-binding domain of the testis-determining gene Sry. Binding of the Sox domain induces a sharp bend in its target DNA, which might serve to bring together other regulatory proteins that are bound to different regions of the DNA molecule.

NOTOCHORD

A rod-like structure of mesodermal origin that is found in vertebrate embryos. It participates in the differentiation of the ventral neural tube and in the specification of motor neurons.

BONE MORPHOGENETIC PROTEIN

(BMP). Molecules of the transforming growth factor-α (TGFα)-family that can induce bone formation and ventralize the vertebrate embryo.

WD REPEAT

A protein sequence motif with a characteristic tryptophan–aspartate repeat.

DOMINANT NEGATIVE

A mutant molecule that blocks or antagonizes the normal function of the unmodified molecule by diverse mechanisms such as heteromerization and competition for partners or for binding sites.

PRIMITIVE STREAK

An elongated depression of reptile, bird and mammalian embryos, through which mesodermal and endodermal cells migrate into the interior of the embryo. The most anterior tip of the primitive streak forms a signalling centre known as the node (Hensen's node in the chick). The streak is functionally homologous to the amphibian blastopore.

PARAXIAL MESODERM

A region of the mesoderm adjacent to the notochord, which becomes segmented rostrocaudally to give rise to the somites early in development.

LYMPHOID-ENHANCER FACTOR/T-CELL FACTOR

(LEF/TCF). Transcription factors of the LEF/TCF family bind to DNA HMG boxes and constitute the most downstream components of the Wnt pathway. Mammals possess four LEF/TCF genes, whereas worms and flies each carry one Tcf gene in their genome.

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Gómez-Skarmeta, J., Campuzano, S. & Modolell, J. Half a century of neural prepatterning: the story of a few bristles and many genes. Nat Rev Neurosci 4, 587–598 (2003). https://doi.org/10.1038/nrn1142

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