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First published online 19 December 2007
doi: 10.1242/dev.011783

Development 135, 473-481 (2008)
Published by The Company of Biologists 2008
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Insm1 (IA-1) is a crucial component of the transcriptional network that controls differentiation of the sympatho-adrenal lineage

Hendrik Wildner1,*, Mathias S. Gierl1,*, Michael Strehle1, Patrick Pla2 and Carmen Birchmeier1,{dagger}

1 Max-Delbrück-Centrum for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
2 UMR 8542 CNRS, Ecole Normale Supérieure, 46, rue d'Ulm, 75230 Paris cedex 05, France.

{dagger} Author for correspondence (e-mail: cbirch{at}mdc-berlin.de)

Accepted 30 October 2007

Insm1 (IA-1) encodes a Zn-finger factor that is expressed in the developing nervous system. We demonstrate here that the development of the sympatho-adrenal lineage is severely impaired in Insm1 mutant mice. Differentiation of sympatho-adrenal precursors, as assessed by the expression of neuronal subtype-specific genes such as Th and Dbh, is delayed in a pronounced manner, which is accompanied by a reduced proliferation. Sympathetic neurons eventually overcome the differentiation blockade and mature correctly, but sympathetic ganglia remain small. By contrast, terminal differentiation of adrenal chromaffin cells does not occur. The transcription factors Mash1 (Ascl1), Phox2a, Gata3 and Hand2 (previously dHand) control the differentiation of sympatho-adrenal precursor cells, and their deregulated expression in Insm1 mutant mice demonstrates that Insm1 acts in the transcriptional network that controls differentiation of this lineage. Pronounced similarities between Mash1 and Insm1 phenotypes are apparent, which suggests that Insm1 might mediate aspects of Mash1 function in the subtype-specific differentiation of sympatho-adrenal precursors. Noradrenaline is the major catecholamine produced by developing sympatho-adrenal cells and is required for fetal survival. We demonstrate that the fetal lethality of Insm1 mutant mice is caused by catecholamine deficiency, which highlights the importance of Insm1 in the development of the sympatho-adrenal lineage.

Key words: Sympatho-adrenal lineage, Chromaffin cells, Sympathetic neurons, Zn-finger transcription factor, Endocrine differentiation, Mash1 (Ascl1)


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