Zac1 Is an Essential Transcription Factor for Cardiac Morphogenesis

Yuasa, Shinsuke; Onizuka, Takeshi; Shimoji, Koki; Ohno, Yohei; Kageyama, Takahiro; Yoon, Sung Han; Egashira, Toru; Seki, Tomohisa; Hashimoto, Hisayuki; Nishiyama, Takahiko; Kaneda, Ruri; Murata, Mitsushige; Hattori, Fumiyuki; Makino, Shinji; Sano, Motoaki; Ogawa, Satoshi; Prall, Owen W.J.; Harvey, Richard P.; Fukuda, Keiichi

doi:10.1161/circresaha.109.214130

Cited by 49 publications

(64 citation statements)

References 29 publications

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“…Misexpression of Zac1 in neocortical progenitors inhibited progenitor maturation, while delaying neuronal differentiation and migration. The effects of Zac1 on neuronal migration were in part mediated by Pac1 ( pituitary adenylate cyclase-activating polypeptide type I receptor), a Zac1 transcriptional target (Ciani et al, 1999;Rodríguez-Henche et al, 2002) that controls neocortical progenitor proliferation (Suh et al, 2001;Yan et al, 2013). We have thus identified a novel Zac1-Pac1 regulatorypathwaythatcontrolsprogenitormaturation,neuronal differentiation, and migration in the developing neocortex.…”

Section: Introductionmentioning

confidence: 84%

Zac1Regulates the Differentiation and Migration of Neocortical Neurons viaPac1

et al. 2015

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Imprinted genes are dosage sensitive, and their dysregulated expression is linked to disorders of growth and proliferation, including fetal and postnatal growth restriction. Common sequelae of growth disorders include neurodevelopmental defects, some of which are indirectly related to placental insufficiency. However, several growth-associated imprinted genes are also expressed in the embryonic CNS, in which their aberrant expression may more directly affect neurodevelopment. To test whether growth-associated genes influence neural lineage progression, we focused on the maternally imprinted gene Zac1. In humans, either loss or gain of ZAC1 expression is associated with reduced growth rates and intellectual disability. To test whether increased Zac1 expression directly perturbs neurodevelopment, we misexpressed Zac1 in murine neocortical progenitors. The effects were striking: Zac1 delayed the transition of apical radial glial cells to basal intermediate neuronal progenitors and postponed their subsequent differentiation into neurons. Zac1 misexpression also blocked neuronal migration, with Zac1-overexpressing neurons pausing more frequently and forming fewer neurite branches during the period when locomoting neurons undergo dynamic morphological transitions. Similar, albeit less striking, neuronal migration and morphological defects were observed on Zac1 knockdown, indicating that Zac1 levels must be regulated precisely. Finally, Zac1 controlled neuronal migration by regulating Pac1 transcription, a receptor for the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP). Pac1 and Zac1 loss-and gain-of-function presented as phenocopies, and overexpression of Pac1 rescued the Zac1 knockdown neuronal migration phenotype. Thus, dysregulated Zac1 expression has striking consequences on neocortical development, suggesting that misexpression of this transcription factor in the brain in certain growth disorders may contribute to neurocognitive deficits.

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Section: Introductionmentioning

confidence: 84%

Zac1Regulates the Differentiation and Migration of Neocortical Neurons viaPac1

et al. 2015

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“…Zac1 null mice are growth retarded and suffer from cardiac malformations and high perinatal lethality due to lung failure (55,61). In contrast, transgenic mice overexpressing ZAC1 present with neonatal hyperglycemia and impaired glucose tolerance in later life (37).…”

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confidence: 99%

Transient Neonatal Diabetes Mellitus Gene Zac1 Impairs Insulin Secretion in Mice through Rasgrf1

Hoffmann

Spengler

2012

Molecular and Cellular Biology

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The biallelic expression of the imprinted gene ZAC1/PLAGL1 underlies ϳ60% of all cases of transient neonatal diabetes mellitus (TNDM) that present with low perinatal insulin secretion. Molecular targets of ZAC1 misexpression in pancreatic ␤ cells are unknown. Here, we identified the guanine nucleotide exchange factor Rasgrf1 as a direct Zac1/Plagl1 target gene in murine ␤ cells. Doubling Zac1 expression reduced Rasgrf1 expression, the stimulus-induced activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, and, ultimately, insulin secretion. Normalizing Rasgrf1 expression reversed this phenotype. Moreover, the transplantation of Zac1-overexpressing ␤ cells failed to reinstate euglycemia in experimental diabetic mice. In contrast, Zac1 expression did not interfere with the signaling of the glucagon-like peptide 1 receptor (GLP-1R), and the GLP-1 analog liraglutide improved hyperglycemia in transplanted experimental diabetic mice. This study unravels a mechanism contributing to insufficient perinatal insulin secretion in TNDM and raises new prospects for therapy.

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“…Such evidence indicated that asymmetric protein distribution produces asymmetric cell division, which has a critical role in maintaining the SC population. In our previous screen for myocyte differentiationpromoting factors 6,7 , we noted markedly elevated expression of granulocyte colony-stimulating factor receptor (G-CSFR, encoded by csf3r) in the developing somite 8 . Furthermore, G-CSFR was transiently expressed in regenerating myocytes of adult injured skeletal muscle, and extrinsic G-CSF supported short-term muscle regeneration in cardiotoxin-induced skeletal muscle injury 9 and crush injury 10 .…”

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confidence: 99%