Overlapping Function of<i>Lmx1a</i>and<i>Lmx1b</i>in Anterior Hindbrain Roof Plate Formation and Cerebellar Growth

Mishima, Yuriko; Lindgren, Anne; Chizhikov, Victor V.; Johnson, Randy L.; Millen, Kathleen J.

doi:10.1523/jneurosci.0969-09.2009

Cited by 64 publications

(74 citation statements)

References 38 publications

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“…5F,G). In addition, the expression patterns of the roof plate marker genes Lmx1a and Lmx1b (Mishima et al, 2009) are intact in the mutant embryos at E9.5 (Fig. 5H,I).…”

Section: Pax3 and Cdx2 Are Transcriptionally Activated By β-Catenin Smentioning

confidence: 96%

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

et al. 2014

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Non-canonical Wnt/planar cell polarity (PCP) signaling plays a primary role in the convergent extension that drives neural tube closure and body axis elongation. PCP signaling gene mutations cause severe neural tube defects (NTDs). However, the role of canonical Wnt/β-catenin signaling in neural tube closure and NTDs remains poorly understood. This study shows that conditional gene targeting of β-catenin in the dorsal neural folds of mouse embryos represses the expression of the homeobox-containing genes Pax3 and Cdx2 at the dorsal posterior neuropore (PNP), and subsequently diminishes the expression of the Wnt/β-catenin signaling target genes T, Tbx6 and Fgf8 at the tail bud, leading to spina bifida aperta, caudal axis bending and tail truncation. We demonstrate that Pax3 and Cdx2 are novel downstream targets of Wnt/β-catenin signaling. Transgenic activation of Pax3 cDNA can rescue the closure defect in the β-catenin mutants, suggesting that Pax3 is a key downstream effector of β-catenin signaling in the PNP closure process. Cdx2 is known to be crucial in posterior axis elongation and in neural tube closure. We found that Cdx2 expression is also repressed in the dorsal PNPs of Pax3-null embryos. However, the ectopically activated Pax3 in the β-catenin mutants cannot restore Cdx2 mRNA in the dorsal PNP, suggesting that the presence of both β-catenin and Pax3 is required for regional Cdx2 expression. Thus, β-catenin signaling is required for caudal neural tube closure and elongation, acting through the transcriptional regulation of key target genes in the PNP.

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“…5F,G). In addition, the expression patterns of the roof plate marker genes Lmx1a and Lmx1b (Mishima et al, 2009) are intact in the mutant embryos at E9.5 (Fig. 5H,I).…”

Section: Pax3 and Cdx2 Are Transcriptionally Activated By β-Catenin Smentioning

confidence: 96%

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

et al. 2014

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“…5A,B) and gives rise to GABAergic interneurons (Hoshino et al, 2005). By contrast, the roof plate comprises nonneural Lmx1a- (Mishima et al, 2009) and Gdf7-positive lineages (Currle et al, 2005) and gives rise to the choroid plexus (Fig. 5A,B).…”

Section: Blurred Lines: Gabaergic and Glutamatergic Progenitor Domainmentioning

confidence: 98%

Development of the cerebellum: simple steps to make a ‘little brain’

Green²,

2014

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The cerebellum is a pre-eminent model for the study of neurogenesis and circuit assembly. Increasing interest in the cerebellum as a participant in higher cognitive processes and as a locus for a range of disorders and diseases make this simple yet elusive structure an important model in a number of fields. In recent years, our understanding of some of the more familiar aspects of cerebellar growth, such as its territorial allocation and the origin of its various cell types, has undergone major recalibration. Furthermore, owing to its stereotyped circuitry across a range of species, insights from a variety of species have contributed to an increasingly rich picture of how this system develops. Here, we review these recent advances and explore three distinct aspects of cerebellar development -allocation of the cerebellar anlage, the significance of transit amplification and the generation of neuronal diversity -each defined by distinct regulatory mechanisms and each with special significance for health and disease.

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“…dr/dr mutant mice (B6C3Fe-a/a-Lmx1a dr-J ; The Jackson Laboratory), Shh Cre/ϩ (Harfe et al, 2004), and Lmx1b floxed (Lmx1b f/f ) mice (Zhao et al, 2006) were genotyped as previously described (Mishima et al, 2009 Tissue analysis. The procedures for whole-mount and section in situ hybridization have been described previously (Conlon and Herrmann, 1993;Schaeren-Wiemers and Gerfin-Moser, 1993).…”

Section: Animals Lmx1amentioning

confidence: 99%

Lmx1a and Lmx1b Function Cooperatively to Regulate Proliferation, Specification, and Differentiation of Midbrain Dopaminergic Progenitors

Yan¹,

Lévesque²,

Claxton³

et al. 2011

J. Neurosci.

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129

143

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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 of mDA neurons. 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. We therefore generated Lmx1a and Lmx1b double mutants. Severe loss of mDA neurons occurred in Lmx1a dr/dr ;Shh Cre/ϩ ;Lmx1b f/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 p27 Kip1 expression. In addition, Lmx1a and Lmx1b also regulate the expression of floor plate genes such as Corin and Slit2 and specification of postmitotic mDA neurons. These defects were more severe with decreasing gene dosage of Lmx1a and Lmx1b or observed only when all four copies of Lmx1a and Lmx1b genes were inactivated. Together, our results demonstrate that Lmx1a and Lmx1b function cooperatively to regulate proliferation, specification, and differentiation of mDA progenitors, including their floor plate-like properties.

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Overlapping Function ofLmx1aandLmx1bin Anterior Hindbrain Roof Plate Formation and Cerebellar Growth

Cited by 64 publications

References 38 publications

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

Development of the cerebellum: simple steps to make a ‘little brain’

Lmx1a and Lmx1b Function Cooperatively to Regulate Proliferation, Specification, and Differentiation of Midbrain Dopaminergic Progenitors

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