A Novel Transmembrane Protein Recruits Numb to the Plasma Membrane during Asymmetric Cell Division

Qin, Hanjuan; Percival‐Smith, Anthony; Liu, Chengjun; Jia, Christina Y.H.; Gloor, Gregory B.; Li, Shawn S.‐C.

doi:10.1074/jbc.m311733200

Cited by 40 publications

(40 citation statements)

References 59 publications

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“…Laterality defects are seen in knockout mice deficient in activin receptor IIB (Acvr2b), a receptor that binds and transduces TGF-␤ signals (32), and mutations in Acvr2b have been observed in heterotaxy patients (1,2). The mapped interval includes another gene of interest, Numb-L, a regulator of Notch signaling (33)(34)(35). Over-expression of znumb in zebrafish embryos has been shown to cause laterality defects associated with the heart tube (36).…”

Section: Discussionmentioning

confidence: 99%

Mouse Model of Heterotaxy with Single Ventricle Spectrum of Cardiac Anomalies

et al. 2008

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Heterotaxy arises from a failure of the embryo to establish normal left-right asymmetry and is known to affect 3% of infants with congenital heart disease. A recessive mutation causing heterotaxy was recovered in a mouse mutagenesis screen focused on congenital heart defects. Homozygote mutants exhibit abnormal situs in the thoracic and abdominal cavities. Dextrocardia, levocardia, or mesocardia was seen together with right pulmonary isomerism and complex structural heart defects in the single ventricle spectrum. A dominant chamber of left ventricular morphology positioned on the left or right is seen together with transposition of the great arteries. Right atrial isomerism with or without total anomalous pulmonary venous connection was observed in half of the mutants. Because ciliary motion at the embryonic node is required for the specification of laterality, we examined the tracheal epithelia of newborn mice as a proxy for the nodal cilia. However, videomicroscopy showed no defect in ciliary motion. Genome scanning using polymorphic microsatellite markers mapped the mutation to a 3.3 Mb interval on mouse chromosome 7. None of the genes previously described for familial heterotaxy were found in this interval, indicating a novel mutation in this mouse model of heterotaxy. (Pediatr Res 63: 9-14, 2008) T he specification of laterality is essential for survival of air breathing mammals because left-right asymmetry associated with the four chamber heart and great vessels is required for the normal separation of pulmonary and systemic circulation. Heterotaxy syndromes involve birth defects in which organ situs in the thoracic and abdominal cavity are altered in a discordant manner. They are associated with 3% of all congenital heart defects (CHD) (1), with the prevalence estimated at 1.4/10,000 births (2). Because a wide spectrum of complex structural heart malformations are frequently seen in conjunction with heterotaxy, the overall prognosis is often poor. Some of the cardiovascular malformations associated with heterotaxy syndromes include transposition of the great arteries, single ventricle defects, anomalous pulmonary venous connection, atrial septal defects, ventricular septal defects, and right ventricular outflow tract obstruction (3). Other associated findings include left-sided or bilobed liver, rightsided stomach with gut malrotation, and a high incidence of midline associated defects such as cleft lip/palate, encephalocele, and renal abnormalities (1,3,4).Despite detailed knowledge of the clinical presentations, the cause(s) of heterotaxy remains largely unknown. Data collected from the Baltimore-Washington Infant Study from 1980 to 1989 showed a potential association with a familial history of malformations (odds ratio ϭ 5.1, 95% confidence interval ϭ 2.0 -12.9), maternal diabetes, and geographic location, suggesting both environmental and genetic contributions to heterotaxy syndromes (5). In addition, it has been reported that approximately 10% of infants with heterotaxy have a family histor...

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Section: Discussionmentioning

confidence: 99%

Mouse Model of Heterotaxy with Single Ventricle Spectrum of Cardiac Anomalies

et al. 2008

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“…In contrast to the organization in deuterostomes, the two protostomal DUOXA-homologs analyzed were not genetically linked to duox; in fruit flies, there is also evidence for a distinct functional speciation. The Drosophila DUOXA-homolog (mol) encodes a plasma membrane protein (mol-PA) implicated in the polarized recruitment of a cytosolic signal mediator (Numb) to the plasma membrane (18). That mol-PA may not cooperate with Drosophila Duox is also suggested by the distinct phenotypes caused by deficiency of mol (memory loss; listed as CG4482 in Ref 19) or Drosophila duox (defective gut immunity) (20).…”

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confidence: 99%

Identification of the Maturation Factor for Dual Oxidase

Grasberger¹,

Refetoff

2006

Journal of Biological Chemistry

298

277

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Dual oxidase 2 (DUOX2), an NADPH:O 2 oxidoreductase flavoprotein, is a component of the thyroid H 2 O 2 generator crucial for hormone synthesis at the apical membrane. Mutations in DUOX2 produce congenital hypothyroidism in humans. However, no functional DUOX-based NADPH oxidase has ever been reconstituted at the plasma membrane of transfected cells. It has been proposed that DUOX retention in the endoplasmatic reticulum (ER) of heterologous systems is due to the lack of an unidentified component required for functional maturation of the enzyme. By data mining of a massively parallel signature sequencing tissue expression data base, we identified an uncharacterized gene named DUOX maturation factor (DUOXA2) arranged head-to-head to and coexpressed with DUOX2. A paralog (DUOXA1) was similarly linked to DUOX1. The genomic rearrangement leading to linkage of ancient DUOX and DUOXA genes could be traced back before the divergence of echinoderms. We demonstrate that co-expression of DUOXA2, an ER-resident transmembrane protein, allows ER-to-Golgi transition, maturation, and translocation to the plasma membrane of functional DUOX2 in a heterologous system. The identification of DUOXA genes has important implications for studies of the molecular mechanisms controlling DUOX expression and the molecular genetics of congenital hypothyroidism.Generation of H 2 O 2 at the apical membrane of thyroid follicular cells is essential for iodination of thyroglobulin by thyroid peroxidase and constitutes the rate-limiting step of thyroid hormone synthesis. Dual oxidases (DUOX1 and DUOX2) 2 appear to constitute the catalytic core of the H 2 O 2 generator (1, 2). They are large homologs of the phagocyte gp91 phox /Nox2 NADPH-dependent oxidase with an N-terminal extension comprising a peroxidase-like domain. Although the crucial role of DUOX2 in thyroid hormonogenesis has been substantiated by reports of severe congenital hypothyroidism in patients with biallelic nonsense mutations (3), the understanding of structure, function, and regulation of DUOX has remained limited. The major obstacle for molecular studies of DUOX is the lack of a suitable heterologous cell system for DUOX-based functional NADPH oxidase expression. Transfected cells completely retain DUOX in the endoplasmatic reticulum (ER) (4 -8), suggesting that an unidentified component, essential for DUOX maturation, may be specifically expressed in tissues containing the functional enzyme. EXPERIMENTAL PROCEDURESData Mining and Computational Analysis-Massively parallel signature sequencing (MPSS) data (9) were obtained from the NCBI Gene Expression Omnibus repository (www.ncbi.nlm.nih.gov/geo/; records GSE1747 and GPL1443). A thyroid specificity score, as defined by Jongeneel et al. (9), was calculated for signatures with frequency Ͼ100 tags per million (ϳ30 mRNA copies/cell) in the thyroid/parathyroid library. Tags with scores ϾϪ1 were mapped to the human genome assembly using BLAST. DUOXA homologs were identified by tBLASTn searches against the NCBI nr data base and trace...

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“…Duox proteins are required for generation of H 2 O 2 during thyroid hormone biosynthesis (13)(14)(15). We previously identified the Numb-interacting protein (Nip) in a screen for proteins that bind to the cell fate determinant Numb (16); however, the role of Nip has not as yet been studied for a function related to cell fate determination. The mammalian homologue Nip1 was subsequently re-identified as Duoxa1, a Duox1 maturation factor (17).…”

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confidence: 99%

Mammalian Numb-interacting Protein 1/Dual Oxidase Maturation Factor 1 Directs Neuronal Fate in Stem Cells

Kennedy¹,

Ostrakhovitch²,

Sandiford³

et al. 2010

Journal of Biological Chemistry

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In this study, we describe a role for the mammalian Numb-interacting protein 1 (Nip1) in regulation of neuronal differentiation in stem cells. The expression of Nip1 was detected in the developing mouse brain, embryonic stem cells, primary neuronal stem cells, and retinoic acid-treated P19 embryonal carcinoma cells. The highest expression of Nip1 was observed in undifferentiated neuronal stem cells and was associated with Duox1-mediated reactive oxygen species ROS production. Ectopic nip1 expression in P19 embryonal carcinoma cells induced neuronal differentiation, and this phenotype was also linked to elevated ROS production. The neuronal differentiation in nip1-overexpressing P19 cells was achieved in a retinoic acid-independent manner and was corroborated by an increase in the expression of the neuronal basic helixloop-helix transcription factors and neural-lineage cell markers. Furthermore, depletion of nip1 by short hairpin RNA led to a decrease in the expression of neuronal basic helix-loop-helix transcription factors and ROS. However, inhibition of ROS production in nip1-overexpressing P19 cells restricted but did not extinguish neuronal differentiation. Microarray and mass spectrometry analysis identified intermediate filaments as the principal cytoskeletal elements affected by up-regulation of nip1. We show here the first evidence for a functional interaction between Nip1 and a component of the nuclear lamina, lamin A/C. associated with a neuronal-specific phenotype. Taken together, our data reveal an important role for Nip1 in the guidance of neuronal differentiation through ROS generation and modulation of intermediate filaments and implicate Nip1 as a novel intrinsic regulator of neuronal cell fate.

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A Novel Transmembrane Protein Recruits Numb to the Plasma Membrane during Asymmetric Cell Division

Cited by 40 publications

References 59 publications

Mouse Model of Heterotaxy with Single Ventricle Spectrum of Cardiac Anomalies

Mouse Model of Heterotaxy with Single Ventricle Spectrum of Cardiac Anomalies

Identification of the Maturation Factor for Dual Oxidase

Mammalian Numb-interacting Protein 1/Dual Oxidase Maturation Factor 1 Directs Neuronal Fate in Stem Cells

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