Patterning of the basal telencephalon and hypothalamus is essential for guidance of cortical projections.
We have investigated the mechanisms that control the guidance of corticofugal projections as they extend along different subdivisions of the forebrain. To this aim, we analyzed the development of cortical projections in mice that lack Nkx2-1, a homeobox gene whose expression is restricted to two domains within the forebrain: the basal telencephalon and the hypothalamus. Molecular respecification of the basal telencephalon and hypothalamus in Nkx2-1-deficient mice causes a severe defect in the guidance of layer 5 cortical projections and ascending fibers of the cerebral peduncle. These axon tracts take an abnormal path when coursing through both the basal telencephalon and hypothalamus. By contrast, loss of Nkx2-1 function does not impair guidance of corticothalamic or thalamocortical axons. In vitro experiments demonstrate that the basal telencephalon and the hypothalamus contain an activity that repels the growth of cortical axons, suggesting that loss of this activity is the cause of the defects observed in Nkx2-1 mutants. Furthermore, analysis of the expression of candidate molecules in the basal telencephalon and hypothalamus of Nkx2-1 mutants suggests that Slit2 contributes to this activity.
Marín
Oscar
O
Department of Psychiatry, Nina Ireland Laboratory of Developmental Neurobiology, Langley Porter Psychiatric Institute, University of California, San Francisco, USA.
Baker
Joshua
J
Puelles
Luis
L
Rubenstein
John L R
JL
D000818:Animals; D001369:Axons / Q000502:physiology; D019521:Body Patterning; D002450:Cell Communication; D004298:Dopamine / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D007031:Hypothalamus / Q000166:cytology / Q000196:embryology*; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D008959:Models, Neurological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000196:embryology*; D016548:Prosencephalon / Q000196:embryology; D011712:Pyramidal Tracts / Q000166:cytology; D013687:Telencephalon / Q000166:cytology / Q000196:embryology*; D000098552:Slit Homolog 2 Protein
D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D000098552:Slit Homolog 2 Protein; D004298:Dopamine