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Proneural genes and the specification of neural cell types

Key Points

  • Genetic studies in Drosophila and vertebrate models have provided evidence that a small number of 'proneural genes', which encode transcription factors of the basic helix–loop–helix (bHLH) class, are both necessary and sufficient to initiate the development of neuronal lineages and to promote the generation of progenitors that are committed to differentiation.

  • Molecular analysis in Drosophila led to the isolation of four genes that regulate the early steps of neural development — achaete (ac), scute (sc), lethal of scute (lsc) and asense (ase). An additional proneural gene, atonal (ato), was identified in a screen to identify bHLH sequences related to that found in achaete-scute complex (asc) genes. Many genes that are related to asc and ato have been found in vertebrates.

  • Proneural proteins bind DNA as heterodimeric complexes that are formed with ubiquitously expressed bHLH proteins, or E proteins, and most of them act as transcriptional activators.

  • Mutation analysis in the mouse has so far established a clear proneural activity for only a few genes, namely Mash1, Ngn1 and Ngn2, and possibly Math1 and Math5. However, these genes do not account for the selection of all neural progenitors, so it is likely that other genes with proneural activity remain to be identified.

  • The mechanisms that underlie proneural function include: activation of the Notch signalling pathway, leading to the inhibition of proneural gene expression in adjacent cells; positive-feedback loops that maintain proneural gene expression; activation of neuronal-differentiation gene cascades that implement neuronal-differentiation programmes; inhibition of glial cell fates; and regulation of the cell cycle.

  • In addition to their role in the initial selection and specification of neural progenitor cells, proneural proteins are also involved in neuronal-subtype specification. Future studies might reveal new roles for proneural genes that will help us to understand the coupling between proneural and subtype-differentiation programmes.

Abstract

Certain morphological, physiological and molecular characteristics are shared by all neurons. However, despite these similarities, neurons constitute the most diverse cell population of any organism. Recently, considerable attention has been focused on identifying the molecular mechanisms that underlie this cellular diversity. Parallel studies in Drosophila and vertebrates have revealed that proneural genes are key regulators of neurogenesis, coordinating the acquisition of a generic neuronal fate and of specific subtype identities that are appropriate for the location and time of neuronal generation. These studies reveal that, in spite of differences between invertebrate and vertebrate neural lineages, Drosophila and vertebrate proneural genes have remarkably similar roles.

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Figure 1: Structure and properties of neural bHLH proteins.
Figure 2: Regulatory pathways controlled by proneural genes in neuronal commitment.
Figure 3: A model of the role of vertebrate proneural genes during the neurogenic and gliogenic phases of neural development.
Figure 4: bHLH proteins in the dorsal spinal cord.
Figure 5: Models of interactions of proneural proteins with cofactors that confer functional specificity.
Figure 6: Context-dependent activity of Mash1 and the neurogenins.

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Acknowledgements

We are grateful to C. Goridis, P. Ramain, C. Schuurmans and U. Strahle for their critical comments on the manuscript, and to G. Gradwohl for his help with figure 1a.

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Correspondence to François Guillemot.

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DATABASES

Flybase

ac

amos

asc

ase

ato

cato

Chip

cut

da

Dacapo

Delta

emc

lsc

myc

MyoD

Notch

Pannier

rho

sc

Senseless

string

LocusLink

BMP2

CBP

Chx10

CNTF

DBH

Delta

E2-2

E2A

Ebf3

Epo

FGF2

GFAP

HEB

Hes1

Hes6

Id

Mash1

Mash2

Math1

Math2/Nex1

Math3/NeuroM

Math5

Max

Myf5

Myog

Myt1

β3 nAChR

NeuroD

NeuroD2

Ngn1

Ngn2

Notch

Olig1

Olig2

p16

p21

p27

p300

Pax6

PCAF

Phox2a

Phox2b

Serrate/Jagged

Smad1

Stat1

Stat3

FURTHER INFORMATION

Encyclopedia of Life Sciences

Drosophila neural development

neural development: bHLH genes

neurogenesis in Drosophila

Glossary

BASIC HELIX–LOOP–HELIX

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

RT-PCR

Reverse transcriptase–polymerase chain reaction (PCR) — a reaction in which messenger RNA is converted into DNA (reverse transcription), which is then amplified by PCR.

YEAST TWO-HYBRID SCREEN

A system used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins; one of them is fused to the GAL4 DNA-binding domain and the other one is fused to the GAL4 activation domain. The two proteins are expressed together in yeast; if they interact, then the resulting complex will drive the expression of a reporter gene, commonly β-galactosidase.

CHORDOTONAL ORGAN

A sense organ in insects that detects mechanical and sound vibrations.

ROOF PLATE

The point of fusion of the neural folds, forming the dorsal-most part of the neural tube.

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.

EPISTASIS

When one gene masks the expression of another. If mutant a gives phenotype A and mutant b gives phenotype B, and if the double mutant ab gives phenotype A and not B, then gene a is epistatic to gene b.

HOMEOBOX

A sequence of about 180 base pairs that encodes a DNA-binding protein sequence known as the homeodomain. The 60-amino-acid homeodomain comprises three α-helices.

IMAGINAL DISC

A single-cell-layer epithelial structure of the Drosophila larva that gives rise to wings, legs and other appendages.

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Bertrand, N., Castro, D. & Guillemot, F. Proneural genes and the specification of neural cell types. Nat Rev Neurosci 3, 517–530 (2002). https://doi.org/10.1038/nrn874

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