Neural crest-specific deletion of Ldb1 leads to cleft secondary palate with impaired palatal shelf elevation

BMC Developmental Biology

Juhee Jeong¹  Veronica Choi¹  Neeti Sharma¹  Yangu Zhao³  Andre Landin Malt¹  Jeffry Cesario¹  Asma Almaidhan² 

[1] Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, 10010 New York, NY, USA;Consortium for Translational Orthodontic Research, New York University College of Dentistry, 10010 New York, NY, USA;Program on Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 20892 Bethesda, MD, USA

关键词: LDB1;    Craniofacial development;    Cleft palate;   

Others  :  1085322
DOI  :  10.1186/1471-213X-14-3

 received in 2013-07-16, accepted in 2014-01-08,  发布年份 2014

【 摘 要 】

Background

LIM domain binding protein 1 (LDB1) is a transcriptional co-factor, which interacts with multiple transcription factors and other proteins containing LIM domains. Complete inactivation of Ldb1 in mice resulted in early embryonic lethality with severe patterning defects during gastrulation. Tissue-specific deletions using a conditional knockout allele revealed additional roles of Ldb1 in the development of the central nervous system, hematopoietic system, and limbs. The goal of the current study was to determine the importance of Ldb1 function during craniofacial development in mouse embryos.

Results

We generated tissue-specific Ldb1 mutants using Wnt1-Cre, which causes deletion of a floxed allele in the neural crest; neural crest-derived cells contribute to most of the mesenchyme of the developing face. All examined Wnt1-Cre;Ldb1^fl/- mutants suffered from cleft secondary palate. Therefore, we performed a series of experiments to investigate how Ldb1 regulated palate development. First, we examined the expression of Ldb1 during normal development, and found that Ldb1 was expressed broadly in the palatal mesenchyme during early stages of palate development. Second, we compared the morphology of the developing palate in control and Ldb1 mutant embryos using sections. We found that the mutant palatal shelves had abnormally blunt appearance, and failed to elevate above the tongue at the posterior domain. An in vitro head culture experiment indicated that the elevation defect was not due to interference by the tongue. Finally, in the Ldb1 mutant palatal shelves, cell proliferation was abnormal in the anterior, and the expression of Wnt5a, Pax9 and Osr2, which regulate palatal shelf elevation, was also altered.

Conclusions

The function of Ldb1 in the neural crest-derived palatal mesenchyme is essential for normal morphogenesis of the secondary palate.

【 授权许可】

   
2014 Almaidhan et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Sauka-Spengler T, Bronner-Fraser M: Development and evolution of the migratory neural crest: a gene regulatory perspective. Curr Opin Genet Dev 2006, 16:360-366.
• [2]Minoux M, Rijli FM: Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development. Development 2010, 137:2605-2621.
• [3]Hsieh EW, Yeh RF, Oberoi S, Vargervik K, Slavotinek AM: Cleft lip with or without cleft palate: frequency in different ethnic populations from the UCSF craniofacial clinic. Am J Med Genet A 2007, 143A:2347-2351.
• [4]Severens JL, Prahl C, Kuijpers-Jagtman AM, Prahl-Andersen B: Short-term cost-effectiveness analysis of presurgical orthopedic treatment in children with complete unilateral cleft lip and palate. Cleft Palate Craniofac J 1998, 35:222-226.
• [5]Mildinhall S: Speech and language in the patient with cleft palate. Front Oral Biol 2012, 16:137-146.
• [6]Bush JO, Jiang R: Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development. Development 2012, 139:231-243.
• [7]Gritli-Linde A: Molecular control of secondary palate development. Dev Biol 2007, 301:309-326.
• [8]Jugessur A, Murray JC: Orofacial clefting: recent insights into a complex trait. Curr Opin Genet Dev 2005, 15:270-278.
• [9]Matthews JM, Visvader JE: LIM-domain-binding protein 1: a multifunctional cofactor that interacts with diverse proteins. EMBO Rep 2003, 4:1132-1137.
• [10]Agulnick AD, Taira M, Breen JJ, Tanaka T, Dawid IB, Westphal H: Interactions of the LIM-domain-binding factor Ldb1 with LIM homeodomain proteins. Nature 1996, 384:270-272.
• [11]Jurata LW, Kenny DA, Gill GN: Nuclear LIM interactor, a rhombotin and LIM homeodomain interacting protein, is expressed early in neuronal development. Proc Natl Acad Sci USA 1996, 93:11693-11698.
• [12]Bach I, Carriere C, Ostendorff HP, Andersen B, Rosenfeld MG: A family of LIM domain-associated cofactors confer transcriptional synergism between LIM and Otx homeodomain proteins. Genes Dev 1997, 11:1370-1380.
• [13]Mukhopadhyay M, Teufel A, Yamashita T, Agulnick AD, Chen L, Downs KM, Schindler A, Grinberg A, Huang SP, Dorward D, Westphal H: Functional ablation of the mouse Ldb1 gene results in severe patterning defects during gastrulation. Development 2003, 130:495-505.
• [14]Zhao Y, Kwan KM, Mailloux CM, Lee WK, Grinberg A, Wurst W, Behringer RR, Westphal H: LIM-homeodomain proteins Lhx1 and Lhx5, and their cofactor Ldb1, control Purkinje cell differentiation in the developing cerebellum. Proc Natl Acad Sci USA 2007, 104:13182-13186.
• [15]Li L, Jothi R, Cui K, Lee JY, Cohen T, Gorivodsky M, Tzchori I, Zhao Y, Hayes SM, Bresnick EH, et al.: Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells. Nat Immunol 2011, 12:129-136.
• [16]Tzchori I, Day TF, Carolan PJ, Zhao Y, Wassif CA, Li L, Lewandoski M, Gorivodsky M, Love PE, Porter FD, et al.: LIM homeobox transcription factors integrate signaling events that control three-dimensional limb patterning and growth. Development 2009, 136:1375-1385.
• [17]Danielian PS, Muccino D, Rowitch DH, Michael SK, McMahon AP: Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr Biol 1998, 8:1323-1326.
• [18]Chai Y, Jiang X, Ito Y, Bringas P Jr, Han J, Rowitch DH, Soriano P, McMahon AP, Sucov HM: Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 2000, 127:1671-1679.
• [19]Tucker AS, Al Khamis A, Ferguson CA, Bach I, Rosenfeld MG, Sharpe PT: Conserved regulation of mesenchymal gene expression by Fgf-8 in face and limb development. Development 1999, 126:221-228.
• [20]Noden DM, Trainor PA: Relations and interactions between cranial mesoderm and neural crest populations. J Anat 2005, 207:575-601.
• [21]Jin JZ, Tan M, Warner DR, Darling DS, Higashi Y, Gridley T, Ding J: Mesenchymal cell remodeling during mouse secondary palate reorientation. Dev Dyn 2010, 239:2110-2117.
• [22]Yu K, Ornitz DM: Histomorphological study of palatal shelf elevation during murine secondary palate formation. Dev Dyn 2011, 240:1737-1744.
• [23]He F, Xiong W, Yu X, Espinoza-Lewis R, Liu C, Gu S, Nishita M, Suzuki K, Yamada G, Minami Y, Chen Y: Wnt5a regulates directional cell migration and cell proliferation via Ror2-mediated noncanonical pathway in mammalian palate development. Development 2008, 135:3871-3879.
• [24]Lan Y, Ovitt CE, Cho ES, Maltby KM, Wang Q, Jiang R: Odd-skipped related 2 (Osr2) encodes a key intrinsic regulator of secondary palate growth and morphogenesis. Development 2004, 131:3207-3216.
• [25]Jin JZ, Li Q, Higashi Y, Darling DS, Ding J: Analysis of Zfhx1a mutant mice reveals palatal shelf contact-independent medial edge epithelial differentiation during palate fusion. Cell Tissue Res 2008, 333:29-38.
• [26]Peters H, Neubuser A, Kratochwil K, Balling R: Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev 1998, 12:2735-2747.
• [27]Zhou J, Gao Y, Lan Y, Jia S, Jiang R: Pax9 regulates a molecular network involving Bmp4, Fgf10, Shh signaling and the Osr2 transcription factor to control palate morphogenesis. Development 2013, 140:4709-4718.
• [28]Ding H, Wu X, Bostrom H, Kim I, Wong N, Tsoi B, O’Rourke M, Koh GY, Soriano P, Betsholtz C, et al.: A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling. Nat Genet 2004, 36:1111-1116.
• [29]Iwata J, Tung L, Urata M, Hacia JG, Pelikan R, Suzuki A, Ramenzoni L, Chaudhry O, Parada C, Sanchez-Lara PA, Chai Y: Fibroblast growth factor 9 (FGF9)-pituitary homeobox 2 (PITX2) pathway mediates transforming growth factor beta (TGFbeta) signaling to regulate cell proliferation in palatal mesenchyme during mouse palatogenesis. J Biol Chem 2012, 287:2353-2363.
• [30]Enomoto H, Nelson CM, Somerville RP, Mielke K, Dixon LJ, Powell K, Apte SS: Cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation. Development 2010, 137:4029-4038.
• [31]Snyder-Warwick AK, Perlyn CA, Pan J, Yu K, Zhang L, Ornitz DM: Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate. Proc Natl Acad Sci USA 2010, 107:2515-2520.
• [32]Li L, Wang Y, Lin M, Yuan G, Yang G, Zheng Y, Chen Y: Augmented BMPRIA-mediated BMP signaling in cranial neural crest lineage leads to cleft palate formation and delayed tooth differentiation. PLoS One 2013, 8:e66107.
• [33]Jiang R, Lan Y, Chapman HD, Shawber C, Norton CR, Serreze DV, Weinmaster G, Gridley T: Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev 1998, 12:1046-1057.
• [34]Alappat SR, Zhang Z, Suzuki K, Zhang X, Liu H, Jiang R, Yamada G, Chen Y: The cellular and molecular etiology of the cleft secondary palate in Fgf10 mutant mice. Dev Biol 2005, 277:102-113.
• [35]Rice R, Spencer-Dene B, Connor EC, Gritli-Linde A, McMahon AP, Dickson C, Thesleff I, Rice DP: Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J Clin Invest 2004, 113:1692-1700.
• [36]Welsh IC, Hagge-Greenberg A, O’Brien TP: A dosage-dependent role for Spry2 in growth and patterning during palate development. Mech Dev 2007, 124:746-761.
• [37]He F, Popkie AP, Xiong W, Li L, Wang Y, Phiel CJ, Chen Y: Gsk3beta is required in the epithelium for palatal elevation in mice. Dev Dyn 2010, 239:3235-3246.
• [38]Goudy S, Law A, Sanchez G, Baldwin HS, Brown C: Tbx1 is necessary for palatal elongation and elevation. Mech Dev 2010, 127:292-300.
• [39]Song Z, Liu C, Iwata J, Gu S, Suzuki A, Sun C, He W, Shu R, Li L, Chai Y, Chen Y: Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development. J Biol Chem 2013, 288:10440-10450.
• [40]Wang C, Chang JY, Yang C, Huang Y, Liu J, You P, McKeehan WL, Wang F, Li X: Type 1 fibroblast growth factor receptor in cranial neural crest cells-derived mesenchyme is required for palatogenesis. J Biol Chem 2013, 288:22174-22183.
• [41]Yumoto K, Thomas PS, Lane J, Matsuzaki K, Inagaki M, Ninomiya-Tsuji J, Scott GJ, Ray MK, Ishii M, Maxson R, et al.: TGF-beta-activated kinase 1 (Tak1) mediates agonist-induced Smad activation and linker region phosphorylation in embryonic craniofacial neural crest-derived cells. J Biol Chem 2013, 288:13467-13480.
• [42]Zhao Y, Guo YJ, Tomac AC, Taylor NR, Grinberg A, Lee EJ, Huang S, Westphal H: Isolated cleft palate in mice with a targeted mutation of the LIM homeobox gene lhx8. Proc Natl Acad Sci USA 1999, 96:15002-15006.
• [43]Jeong J, Cesario J, Zhao Y, Burns L, Westphal H, Rubenstein JL: Cleft palate defect of Dlx1/2−/− mutant mice is caused by lack of vertical outgrowth in the posterior palate. Dev Dyn 2012, 241:1757-1769.
• [44]Denaxa M, Sharpe PT, Pachnis V: The LIM homeodomain transcription factors Lhx6 and Lhx7 are key regulators of mammalian dentition. Dev Biol 2009, 333:324-336.
• [45]Sandell LL, Kurosaka H, Trainor PA: Whole mount nuclear fluorescent imaging: convenient documentation of embryo morphology. Genesis 2012, 50:844-850.