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First published online June 19, 2009
doi: 10.1242/10.1242/dev.034546

Development 136, 2477-2485 (2009)
Published by The Company of Biologists 2009
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Insm1 (IA-1) is an essential component of the regulatory network that specifies monoaminergic neuronal phenotypes in the vertebrate hindbrain

John Jacob1,2,{dagger}, Robert Storm3,*, Diogo S. Castro1,*, Christopher Milton1, Patrick Pla4, François Guillemot1, Carmen Birchmeier3 and James Briscoe1,{dagger}

1 MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
2 National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
3 Max-Delbrück-Centrum for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
4 CNRS UMR 8542, Département de Biologie, École Normale Supérieure, 46 rue d'Ulm, 75230, Paris, Cedex 05, France.

{dagger} Authors for correspondence (e-mails:jjacob{at}nimr.mrc.ac.uk; jbrisco{at}nimr.mrc.ac.uk)

Accepted 6 May 2009

Monoaminergic neurons include the physiologically important central serotonergic and noradrenergic subtypes. Here, we identify the zinc-finger transcription factor, Insm1, as a crucial mediator of the differentiation of both subtypes, and in particular the acquisition of their neurotransmitter phenotype. Insm1 is expressed in hindbrain progenitors of monoaminergic neurons as they exit the cell cycle, in a pattern that partially overlaps with the expression of the proneural factor Ascl1. Consistent with this, a conserved cis-regulatory sequence associated with Insm1 is bound by Ascl1 in the hindbrain, and Ascl1 is essential for the expression of Insm1 in the ventral hindbrain. In Insm1-null mutant mice, the expression of the serotonergic fate determinants Pet1, Lmx1b and Gata2 is markedly downregulated. Nevertheless, serotonergic precursors begin to differentiate in Insm1 mutants, but fail to produce serotonin because of a failure to activate expression of tryptophan hydroxylase 2 (Tph2), the key enzyme of serotonin biosynthesis. We find that both Insm1 and Ascl1 coordinately specify Tph2 expression. In brainstem noradrenergic centres of Insm1 mutants, expression of tyrosine hydroxylase is delayed in the locus coeruleus and is markedly deficient in the medullary noradrenergic nuclei. However, Insm1 is dispensable for the expression of a second key noradrenergic biosynthetic enzyme, dopamine β-hydroxylase, which is instead regulated by Ascl1. Thus, Insm1 regulates the synthesis of distinct monoaminergic neurotransmitters by acting combinatorially with, or independently of, Ascl1 in specific monoaminergic populations.

Key words: Hindbrain, Neuron, Serotonin, Noradrenaline, Mouse


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