title: Sim1 and Sim2 are required for the correct targeting of mammillary body axons.
abstract: 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.
authors.affiliation: Research Center, Hôpital Sainte-Justine, 3175 Cote Ste-Catherine, Montréal, Quebec H3T 1C5, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Marion
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.forename: Aurore
authors.initials: A
authors.lastname: Caqueret
authors.forename: Francine
authors.initials: F
authors.lastname: Boucher
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D018628:Gene Dosage; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008326:Mammillary Bodies / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013681:Tegmentum Mesencephali / Q000002:abnormalities / Q000196:embryology; D013788:Thalamus / Q000002:abnormalities / Q000196:embryology; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D012097:Repressor Proteins; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C118348:Robo3 protein, mouse; C101750:Sim1 protein, mouse; C486578:Sim2 protein, mouse; C120010:Slit1 protein, mouse