TY - JOUR
T1 - Lmx1a and Lmx1b function cooperatively to regulate proliferation, specification, and differentiation of midbrain dopaminergic progenitors
AU - Yan, Carol H.
AU - Levesque, Martin
AU - Claxton, Suzanne
AU - Johnson, Randy L.
AU - Ang, Siew Lan
PY - 2011/8/31
Y1 - 2011/8/31
N2 - LIM homeodomain transcription factors, Lmx1a and Lmx1b, are required for the development of midbrain dopaminergic (mDA) neurons. Lmx1b is required for the specification and maintenance of mDA neurons, primarily due to its role in isthmic organizer development that is essential for the induction of mDA neurons. Here, we conditionally deleted Lmx1b in the ventral neural tube using ShhCre and found that Lmx1b conditional mutant mouse embryos show no defect in the development and maintenance ofmDAneurons. In addition, Dreher (Lmx1a mutant) embryos display only a moderate reduction in the number of mDA neurons, suggesting that the related family member Lmx1b might compensate for Lmx1a function.Wetherefore generated Lmx1a and Lmx1b double mutants. Severe loss of mDA neurons occurred in Lmx1adr/dr;ShhCre/+;Lmx1bf/f double mutants due to essential roles for Lmx1a and Lmx1b in regulating the proliferation and neuronal commitment of mDA progenitors through the expression of Wnt1 and Ngn2, respectively. Lmx1a and Lmx1b also negatively regulate Hes1 expression and consequently cell cycle exit through activation of p27Kip1 expression. In addition, Lmx1a and Lmx1b also regulate the expression of floor plate genes such as Corin and Slit2 and specification of postmitoticmDAneurons. These defects were more severe with decreasing gene dosage of Lmx1a and Lmx1b or observed only when all four copies of Lmx1a and Lmx1bgenes were inactivated. Together, our results demonstrate thatLmx1aandLmx1bfunction cooperatively to regulate proliferation, specification, and differentiation of mDA progenitors, including their floor plate-like properties.
AB - LIM homeodomain transcription factors, Lmx1a and Lmx1b, are required for the development of midbrain dopaminergic (mDA) neurons. Lmx1b is required for the specification and maintenance of mDA neurons, primarily due to its role in isthmic organizer development that is essential for the induction of mDA neurons. Here, we conditionally deleted Lmx1b in the ventral neural tube using ShhCre and found that Lmx1b conditional mutant mouse embryos show no defect in the development and maintenance ofmDAneurons. In addition, Dreher (Lmx1a mutant) embryos display only a moderate reduction in the number of mDA neurons, suggesting that the related family member Lmx1b might compensate for Lmx1a function.Wetherefore generated Lmx1a and Lmx1b double mutants. Severe loss of mDA neurons occurred in Lmx1adr/dr;ShhCre/+;Lmx1bf/f double mutants due to essential roles for Lmx1a and Lmx1b in regulating the proliferation and neuronal commitment of mDA progenitors through the expression of Wnt1 and Ngn2, respectively. Lmx1a and Lmx1b also negatively regulate Hes1 expression and consequently cell cycle exit through activation of p27Kip1 expression. In addition, Lmx1a and Lmx1b also regulate the expression of floor plate genes such as Corin and Slit2 and specification of postmitoticmDAneurons. These defects were more severe with decreasing gene dosage of Lmx1a and Lmx1b or observed only when all four copies of Lmx1a and Lmx1bgenes were inactivated. Together, our results demonstrate thatLmx1aandLmx1bfunction cooperatively to regulate proliferation, specification, and differentiation of mDA progenitors, including their floor plate-like properties.
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U2 - 10.1523/JNEUROSCI.1077-11.2011
DO - 10.1523/JNEUROSCI.1077-11.2011
M3 - Article
C2 - 21880902
AN - SCOPUS:80052382699
SN - 0270-6474
VL - 31
SP - 12413
EP - 12425
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 35
ER -