Delayed dopaminergic neuron differentiation in Lrp6 mutant mice.
Wnts are known to bind and activate multiple membrane receptors/coreceptors and to regulate dopaminergic (DA) neuron development and ventral midbrain (VM) morphogenesis. The low density lipoprotein receptor-related protein (Lrp6) is a Wnt co-receptor, yet it remains unclear whether Lrp6 is required for DA neuron development or VM morphogenesis. Lrp6 is expressed ubiquitously in the developing VM. In this study, we show that Lrp6(-/-) mice exhibit normal patterning, proliferation and cell death in the VM, but display a delay in the onset of DA precursor differentiation. A transient 50% reduction in tyrosine hydroxylase-positive DA neurons and in the expression of DA markers such as Nurr1 and Pitx3, as well as a defect in midbrain morphogenesis was detected in the mutant embryos at embryonic day 11.5. Our results, therefore, suggest a role for Lrp6 in the onset of DA neuron development in the VM as well as a role in midbrain morphogenesis.
Laboratory of Molecular Neurobiology, Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Gonçalo
G
Castelo-Branco
Emma R
ER
Andersson
Eleonora
E
Minina
Kyle M
KM
Sousa
Diogo
D
Ribeiro
Chikara
C
Kokubu
Kenji
K
Imai
Nilima
N
Prakash
Wolfgang
W
Wurst
Ernest
E
Arenas
D000818:Animals; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D005838:Genotype; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008636:Mesencephalon / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009024:Morphogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018398:Homeodomain Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; C433629:homeobox protein PITX3; D014446:Tyrosine 3-Monooxygenase; D001973:Bromodeoxyuridine; D004298:Dopamine