Interactions of Wnt/beta-catenin signaling and sonic hedgehog regulate the neurogenesis of ventral midbrain dopamine neurons.
Signaling mechanisms involving Wnt/beta-catenin and sonic hedgehog (Shh) are known to regulate the development of ventral midbrain (vMB) dopamine neurons. However, the interactions between these two mechanisms and how such interactions can be targeted to promote a maximal production of dopamine neurons are not fully understood. Here we show that conditional mouse mutants with region-specific activation of beta-catenin signaling in vMB using the Shh-Cre mice show a marked expansion of Sox2-, Ngn2-, and Otx2-positive progenitors but perturbs their cell cycle exit and reduces the generation of dopamine neurons. Furthermore, activation of beta-catenin in vMB also results in a progressive loss of Shh expression and Shh target genes. Such antagonistic effects between the activation of Wnt/beta-catenin and Shh can be recapitulated in vMB progenitors and in mouse embryonic stem cell cultures. Notwithstanding these antagonistic interactions, cell-type-specific activation of beta-catenin in the midline progenitors using the tyrosine hydroxylase-internal ribosomal entry site-Cre (Th-IRES-Cre) mice leads to increased dopaminergic neurogenesis. Together, these results indicate the presence of a delicate balance between Wnt/beta-catenin and Shh signaling mechanisms in the progression from progenitors to dopamine neurons. Persistent activation of beta-catenin in early progenitors perturbs their cell cycle progression and antagonizes Shh expression, whereas activation of beta-catenin in midline progenitors promotes the generation of dopamine neurons.
Tang
Mianzhi
M
Department of Pathology, University of California, San Francisco and Pathology Service, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Villaescusa
J Carlos
JC
Luo
Sarah X
SX
Guitarte
Camilla
C
Lei
Simonia
S
Miyamoto
Yasunori
Y
Taketo
Makoto M
MM
Arenas
Ernest
E
Huang
Eric J
EJ
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology* / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; C473711:Chir 99021; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C532621:NuiP protein, mouse; D011725:Pyridines; D011743:Pyrimidines; C465570:Shh protein, mouse; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051176:beta Catenin; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase; D001973:Bromodeoxyuridine; D004298:Dopamine