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First published online 16 November 2005
doi: 10.1242/dev.02142

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Sim1 and Sim2 are required for the correct targeting of mammillary body axons

Research Center, Hôpital Sainte-Justine, 3175 Cote Ste-Catherine, Montréal, Quebec H3T 1C5, Canada

^* Author for correspondence (e-mail: jacques.michaud{at}recherche-ste-justine.qc.ca)

Accepted 4 October 2005

The mammillary body (MB), and its axonal projections to the thalamus (mammillothalamic tract, MTT) and the tegmentum (mammillotegmental tract, MTEG), are components of a circuit involved in spatial learning. The bHLH-PAS transcription factors SIM1 and SIM2 are co-expressed in the developing MB. We have found that MB neurons are generated and that they survive at least until E18.5 in embryos lacking both Sim1 and Sim2 (Sim1^-/-;Sim2^-/-). However, the MTT and MTEG are histologically absent in Sim1^-/-;Sim2^-/- embryos, and are reduced in embryos lacking Sim1 but bearing one or two copies of Sim2, indicating a contribution of the latter to the development of MB axons. We have generated, by homologous recombination, a null allele of Sim1 (Sim1^tlz) in which the tau-lacZ fusion gene was introduced, allowing the staining of MB axons. Consistent with the histological studies, lacZ staining showed that the MTT/MTEG is barely detectable in Sim1^tlz/tlz;Sim2^+/- and Sim1^tlz/tlz;Sim2^-/- brains. Instead, MB axons are splayed and grow towards the midline. Slit1 and Slit2, which code for secreted molecules that induce the repulsion of ROBO1-producing axons, are expressed in the midline at the level of the MB, whereas Robo1 is expressed in the developing MB. The expression of Rig-1/Robo3, a negative regulator of Slit signalling, is upregulated in the prospective MB of Sim1/Sim2 double mutants, raising the possibility that the growth of mutant MB axons towards the midline is caused by a decreased sensitivity to SLIT. Finally, we found that Sim1 and Sim2 act along compensatory, but not hierarchical, pathways, suggesting that they play similar roles in vivo.

Key words: Hypothalamus, Transcription factor, Mammillary body, Mouse, Sim1, Sim2

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