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N-terminal fatty-acylation of sonic hedgehog enhances the induction of rodent ventral forebrain neurons

¹ Program in Neurobiology and Department of Pediatrics, Box 209, Children’s Memorial Institute for Research and Education, Northwestern University Medical School, 2430 N. Halsted, Chicago, IL 60614, USA
² Developmental Genetics and the Department of Cell Biology, Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
³ Biogen, 14 Cambridge Center, Cambridge, MA 02142, USA

*Author for correspondence (e-mail: j-kohtz{at}northwestern.edu)

Accepted April 8, 2001

The adult basal ganglia arise from the medial and lateral ganglionic eminences, morphologically distinct structures found in the embryonic telencephalon. We have previously shown that temporal changes in sonic hedgehog (Shh) responsiveness determine the sequential induction of embryonic neurons that populate the medial and lateral ganglionic eminences. In this report, we show that Shh-mediated differentiation of neurons that populate the lateral ganglionic eminence express different combinations of the homeobox-containing transcription factors Dlx, Mash1 and Islet 1/2. Furthermore, we show that N-terminal fatty-acylation of Shh significantly enhances its ability to induce the differentiation of rat E11 telencephalic neurons expressing Dlx, Islet 1/2 or Mash1. Recent evidence indicates that in utero injection of the E9.5 mouse forebrain with retroviruses encoding wild-type Shh induces the ectopic expression of Dlx2 and severe deformities in the brain. In this report, we show that Shh containing a mutation at the site of acylation prevents either of these phenotypes. These results suggest that N-terminal fatty-acylation of Shh may play an important role in Shh-dependent signaling during rodent ventral forebrain formation.

Key words: Sonic hedgehog, Forebrain, Telencephalon, Fatty-acylation, Rat

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