PITX2 is required for normal development of neurons in the mouse subthalamic nucleus and midbrain

Martin, Donna M.; Skidmore, Jennifer; Philips, Steven; Vieira, Claudia; Gage, Philip J.; Condie, Brian G.; Raphael, Yehoash; Martı́nez, Salvador; Camper, Sally A.

doi:10.1016/j.ydbio.2003.10.035

Cited by 93 publications

(134 citation statements)

References 56 publications

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“…Second, regulatory domains in the human and mouse Gad1 gene contain binding sequences for the UNC-30 class of homeodomain proteins and the mouse Gad1 promoter is activated in neuroblastoma cells cotransfected with expression vectors containing unc-30 or Pitx2 cDNAs [8]. However, recently published Pitx2 knockout mice were shown to have grossly normal GABA expression [38]. Therefore, if the function of Pitx2 for specifying GABA neuronal identity is conserved with UNC-30, then Pitx2 is likely to be acting redundantly with Pitx1 or Pitx3, or with another transcription factor.…”

Section: Unc-47: What Protein Is the Vesicular Gaba Transporter?mentioning

confidence: 99%

“…Both unc-25 and unc-47 mutants have normal axon morphology and a normal distribution of synaptic vesicles [15,18]. Interestingly, it was recently shown that Pitx2 knockout mice have defects in axon migration in midbrain neurons, including GABA neurons, suggesting a possible conservation of this role for UNC-30 and Pitx2 [38]. Identification of targets of UNC-30 regulation will be of great interest because these genes are required specifically for GABA neuron outgrowth and synapse formation.…”

Section: Unc-47: What Protein Is the Vesicular Gaba Transporter?mentioning

confidence: 99%

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The GABA nervous system in C. elegans

Schuske

Beg

Jørgensen

2004

Trends in Neurosciences

161

149

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GABA neurotransmission requires a specialized set of proteins to synthesize, transport or respond to GABA. This article reviews results from a genetic strategy in the nematode Caenorhabditis elegans designed to identify the genes responsible for these activities. These studies identified mutations in genes encoding five different proteins: the biosynthetic enzyme for GABA, the vesicular GABA transporter, a transcription factor that determines GABA neuron identity, a classic inhibitory GABA receptor and a novel excitatory GABA receptor. This review discusses the strategy employed to identify these genes as well as the conclusions about GABA transmission derived from study of the mutant phenotypes.Activity in the vertebrate brain depends on a yin and yang balance between excitatory and inhibitory neurotransmission. A deficit of excitatory neurotransmission will lead to unconsciousness; a deficit of inhibitory neurotransmission will lead to epileptic seizures. The most abundant inhibitory neurotransmitter in the brain is GABA. Normal GABA function requires specialized proteins such as biosynthetic enzymes, transporters and receptors. Defects in these proteins can lead to a specific imbalance of GABA neurotransmission and lead to diseases. For example, mutations in the a1 and g2 GABA receptor subunits can cause familial forms of epilepsy [1 -3].Over ten years ago, a strategy was devised to identify the proteins specialized for GABA function using a genetic approach in the nematode Caenorhabditis elegans [4,5]. These studies have lead to some important discoveries. Specifically, the vesicular GABA transporter (VGAT) was first discovered in C. elegans and this sequence was used to identify the mammalian homolog [6]. The homeodomain protein UNC-30 identified a class of transcription factors required for multiple aspects of GABA neuron identity [7,8]. These studies also revealed the first cation-selective GABA receptor [9]. This review will discuss first the strategy used to identify proteins required for GABA neurotransmission in C. elegans and then the impact that their discovery has had on our understanding of GABA function. StrategyTo define the proteins required for GABA function, McIntire and colleagues looked for mutations in the nematode C. elegans that specifically disrupted GABAmediated behaviors [4,5]. To identify the GABA-containing cells in C. elegans, animals were stained using antibodies against the neurotransmitter. Antibody staining revealed that 26 of the 302 neurons present in C. elegans express the neurotransmitter GABA (Figure 1a). These 26 GABApositive neurons comprise six DD neurons, 13 VD neurons, four RME neurons, an RIS neuron, an AVL neuron and a DVB neuron (Figure 1b). These neurons fall into different classes based on their synaptic outputs: the D-type neurons -that is, the DD and VD motor neuronsinnervate the dorsal and ventral body muscles, respectively; the RME motor neurons innervate the head muscles; the AVL and DVB motor neurons innervate the enteric muscles; and RIS is an interneuron ...

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Section: Unc-47: What Protein Is the Vesicular Gaba Transporter?mentioning

confidence: 99%

Section: Unc-47: What Protein Is the Vesicular Gaba Transporter?mentioning

confidence: 99%

The GABA nervous system in C. elegans

Schuske

Beg

Jørgensen

2004

Trends in Neurosciences

161

149

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“…12,13 In addition, Pitx2 is important for hindlimb development, 14 and has been suggested to regulate terminal neuronal differentiation in the developing mouse thalamus and midbrain. 15 Most mutations in human patients decrease DNA binding, transactivation, or both, when tested in cell culture or in vitro. 3,5 Among the mutations found in PITX2 that cause Axenfeld-Rieger syndrome, there is one, V45L, with increased transactivation properties.…”

mentioning

confidence: 99%

PITX2 Gain-of-Function in Rieger Syndrome Eye Model

Holmberg

Liu²,

Hjalt

2004

The American Journal of Pathology

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The human autosomal-dominant disorder AxenfeldRieger syndrome presents with defects in development of the eyes, teeth, and umbilicus. The eye manifests with iris ruptures, irido-corneal adhesions, cloudy corneas, and glaucoma. Transcription factors such as PITX2 and FOXC1 have been found to carry point mutations, causing the disorder. However, for ϳ40% of the cases, the pathogenesis is unknown. It has been reported that some mutations in PITX2 increase transactivation, whereas most mutations cause defects in DNA binding or transactivation. It is not known whether up-regulation of PITX2 activity can cause the disorder as well. Here we test this hypothesis directly by overexpressing PITX2A as a transgene in mouse corneal mesenchyme and iris, using keratocan-flanking sequences. The mice presented with corneal opacification, corneal hypertrophy, irido-corneal adhesions, and severely degenerated retina, resembling glaucoma. The corneal hypertrophy also resembles the corneal hypertrophy of Pitx2؊/؊ mice. Control transgenic mice carrying point mutations T68P or K88E in PITX2A were normal. These findings indicate a novel pathogenetic mechanism in which excess corneal and iridal PITX2A cause glaucoma and anterior defects that closely resemble Axenfeld-Rieger syndrome. Glaucoma is the most common cause of blindness.

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“…However, analysis of the embryonic brain of mice lacking Pitx2 function suggests that Pitx2 regulates neuronal differentiation in the developing ventrolateral thalamus and superior colliculus of the midbrain. 22 We recently examined a family with a heterozygous PITX2 mutation and found brain abnormalities including an enlarged cisterna magna together with an executive skill deficit, which supports the idea that this gene may be important for brain development. 17 The mutation in the homeobox was predicted to abolish DNA binding activity and act in the same way as many other reported mutations.…”

Section: Expression Of Asd Genesmentioning

confidence: 58%

“…One of the other interesting sites of Pitx2 expression is the developing brain, 22 although its function in the brain is not well studied due to the embryonic lethality of homozygous Pitx2 mutations;. However, analysis of the embryonic brain of mice lacking Pitx2 function suggests that Pitx2 regulates neuronal differentiation in the developing ventrolateral thalamus and superior colliculus of the midbrain.…”

Section: Expression Of Asd Genesmentioning

confidence: 99%

Molecular and developmental mechanisms of anterior segment dysgenesis

Sowden

2007

Eye

135

102

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Anterior segment dysgenesis (ASD) is a failure of the normal development of the tissues of the anterior segment of the eye. It leads to anomalies in the structure of the mature anterior segment, associated with an increased risk of glaucoma and corneal opacity. Several different gene mutations have been identified underlying these anomalies with the majority of ASD genes encoding transcriptional regulators. In this review, the role of the ASD genes, PITX2 and FOXC1, is considered in relation to the embryology of the anterior segment, the biochemical function of these proteins, and their role in development and disease aetiology. The emerging view is that these genes act in concert to specify a population of mesenchymal progenitor cells, mainly of neural crest origin, as they migrate anteriorly around the embryonic optic cup. These same genes then regulate mesenchymal cell differentiation to give rise to distinct anterior segment tissues. Development appears critically sensitive to gene dosage, and variation in the normal level of transcription factor activity causes a range of anterior segment anomalies. Interplay between PITX2 and FOXC1 in the development of different anterior segment tissues may partly explain the phenotypic variability and the genetic heterogeneity characteristic of ASD.

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PITX2 is required for normal development of neurons in the mouse subthalamic nucleus and midbrain

Cited by 93 publications

References 56 publications

The GABA nervous system in C. elegans

The GABA nervous system in C. elegans

PITX2 Gain-of-Function in Rieger Syndrome Eye Model

Molecular and developmental mechanisms of anterior segment dysgenesis

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