Neurogenin1 is a determinant of zebrafish basal forebrain dopaminergic neurons and is regulated by the conserved zinc finger protein Tof/Fezl

doi:10.1073/pnas.0600337103

Neurogenin1 is a determinant of zebrafish basal forebrain dopaminergic neurons and is regulated by the conserved zinc finger protein Tof/Fezl

*Department of Biopharmaceutical Sciences, Programs in Human Genetics and Biological Sciences, University of California, San Francisco, CA 94143; and
^‡Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom

Edited by Yuh Nung Jan, University of California School of Medicine, San Francisco, CA, and approved February 9, 2006
↵ ^†Z.E. and S.M. contributed equally to this work. (received for review January 12, 2006)

Abstract

The development of vertebrate basal forebrain dopaminergic (DA) neurons requires the conserved zinc finger protein Too Few (Tof/Fezl) in zebrafish. However, how Tof/Fezl regulates the commitment and differentiation of these DA neurons is not known. Proneural genes encoding basic helix–loop–helix transcription factors regulate the development of multiple neuronal lineages, but their involvement in vertebrate DA neuron determination is unclear. Here we show that neurogenin 1 (ngn1), a vertebrate proneural gene related to the Drosophila atonal, is expressed in and required for specification of DA progenitor cells, and when overexpressed leads to supernumerary DA neurons in the forebrain of zebrafish. Overexpression of ngn1 is also sufficient to induce tyrosine hydroxylase expression in addition to the pan-neuronal marker Hu in nonneural ectoderm. We further show that Tof/Fezl is required to establish basal forebrain ngn1-expressing DA progenitor domains. These findings identify Ngn1 as a determinant of brain DA neurons and provide insights into how Tof/Fezl regulates the development of these clinically important neuronal types.

Footnotes

^§To whom correspondence should be addressed. E-mail: suguo{at}itsa.ucsf.edu
Author contributions: J.-Y.J. and S.G. designed research; J.-Y.J., Z.E., S.M., S.L., B.L., and M.M. performed research; J.-Y.J., Z.E., S.M., M.M., S.W.W., and S.G. analyzed data; and J.-Y.J. and S.G. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

DA,

dopaminergic;

TH,

tyrosine hydroxylase;

hpf,

hours postfertilization;

DAT,

dopamine transporter;

5HT,

serotonin;

MO,

morpholino