Embryo, Nonmammalian; Germ Layers; Notochord; Organizers, Embryonic; Neural Plate
Our laboratory is interested in understanding congenital birth defects. Many children are born with various birth defects including defects of the heart, brain, lungs, and face. These birth defects often require surgery and can be difficult to treat for the child. We hope to discover the genes that lead to these birth defects with the hope of improving our understanding of how human development (embryology) occurs.
Extensive Research Description
My laboratory is interested in the problem of birth defects that occur when embryonic patterning fails to occur properly. A fertilized egg must activate a complex genetic program in order to form functional adult structures. Failure to do so correctly leads to congenital malformations in children, the main cause of infant mortality in the US. We are particularly interested in cellular signals and transcriptional regulation that lead to particular fate changes that specify new tissue types during development. We are also interested in morphogenesis that provides shape to the developing embryo.
Our main approach is to analyze genes identified in infants and children that have birth defects.
We focus on Xenopus as a model system because it is the most closely related human model that is easily and rapidly manipulated. Also there are many congenital malformation genes to analyze and the low cost of Xenopus allows us to study many of these genes by engaging in high-throughput screens. Our main focus is:
- Analysis of human mutations using Xenopus In collaboration with Lifton and Brueckner labs, we have identified a number of genes that are mutated in patients that have congenital heart disease, a failure to properly pattern the heart. We have validated a number of these genes by showing that they also cause abnormal development of frog hearts and are now analyzing the mechanisms of their development. Many of these genes are novel and identifying their mechanisms of cardiac morphogenesis will lead to new understanding of congenital malformations and the underlying developmental biology. We are looking to expand to other organ systems as well including the patterning of the face and other organ systems.
The ribosome biogenesis factor Nol11 is required for optimal rDNA transcription and craniofacial development in Xenopus.
Griffin JN, Sondalle SB, Del Viso F, Baserga SJ, Khokha MK. The ribosome biogenesis factor Nol11 is required for optimal rDNA transcription and craniofacial development in Xenopus. PLoS Genet. 2015 Mar 10;11(3):e1005018.
Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.
Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, Overton J, Meffre E, Khokha MK, Huttner AJ, West B, Podoltsev NA, Boggon TJ, Kazmierczak BI, Lifton RP. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet. 2014 Oct;46(10):1135-9.
The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality.
Boskovski MT, Yuan S, Pedersen NB, Goth CK, Makova S, Clausen H, Brueckner M, Khokha MK. Nature. 2013 Dec 19;504(7480):456-9.
Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning.
Fakhro KA, Choi M, Ware SM, Belmont JW, Towbin JA, Lifton RP, Khokha MK, Brueckner M. PNAS. 2011 Jan 31.
Full List of PubMed Publications
- Griffin JN, Del Viso F, Duncan AR, Robson A, Hwang W, Kulkarni S, Liu KJ, Khokha MK: RAPGEF5 Regulates Nuclear Translocation of β-Catenin. Dev Cell. 2018 Jan 22; 2017 Dec 28. PMID: 29290587
- Moreno-Mateos MA, Fernandez JP, Rouet R, Vejnar CE, Lane MA, Mis E, Khokha MK, Doudna JA, Giraldez AJ: CRISPR-Cpf1 mediates efficient homology-directed repair and temperature-controlled genome editing. Nat Commun. 2017 Dec 8; 2017 Dec 8. PMID: 29222508
- Pierce RW, Merola J, Lavik JP, Kluger MS, Huttner A, Khokha MK, Pober JS: A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome. J Exp Med. 2017 Dec 4; 2017 Nov 2. PMID: 29097442
- Gamm UA, Huang BK, Mis EK, Khokha MK, Choma MA: Visualization and quantification of injury to the ciliated epithelium using quantitative flow imaging and speckle variance optical coherence tomography. Sci Rep. 2017 Nov 8; 2017 Nov 8. PMID: 29118359
- Forouzmand E, Owens NDL, Blitz IL, Paraiso KD, Khokha MK, Gilchrist MJ, Xie X, Cho KWY: Developmentally regulated long non-coding RNAs in Xenopus tropicalis. Dev Biol. 2017 Jun 15; 2016 Jul 12. PMID: 27418388
- Garfinkel AM, Khokha MK: An interspecies heart-to-heart: Using Xenopus to uncover the genetic basis of congenital heart disease. Curr Pathobiol Rep. 2017 Jun; 2017 May 6. PMID: 29082114
- Deniz E, Jonas S, Hooper M, N Griffin J, Choma MA, Khokha MK: Analysis of Craniocardiac Malformations in Xenopus using Optical Coherence Tomography. Sci Rep. 2017 Feb 14; 2017 Feb 14. PMID: 28195132
- Khokha MK, Mitchell LE, Wallingford JB: An opportunity to address the genetic causes of birth defects. Pediatr Res. 2017 Feb; 2016 Nov 3. PMID: 27925620
- Khokha MK, Mitchell LE, Wallingford JB: White paper on the study of birth defects. Birth Defects Res. 2017 Jan 30; 2017 Jan 27. PMID: 28398650
- Robson A, Owens ND, Baserga SJ, Khokha MK, Griffin JN: Expression of ribosomopathy genes during Xenopus tropicalis embryogenesis. BMC Dev Biol. 2016 Oct 26; 2016 Oct 26. PMID: 27784267
- Sencan I, Huang BK, Bian Y, Mis E, Khokha MK, Cao H, Choma M: Ultrahigh-speed, phase-sensitive full-field interferometric confocal microscopy for quantitative microscale physiology. Biomed Opt Express. 2016 Nov 1; 2016 Oct 20. PMID: 27896006
- Bazzini AA, Del Viso F, Moreno-Mateos MA, Johnstone TG, Vejnar CE, Qin Y, Yao J, Khokha MK, Giraldez AJ: Codon identity regulates mRNA stability and translation efficiency during the maternal-to-zygotic transition. EMBO J. 2016 Oct 4; 2016 Jul 19. PMID: 27436874
- Del Viso F, Huang F, Myers J, Chalfant M, Zhang Y, Reza N, Bewersdorf J, Lusk CP, Khokha MK: Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia. Dev Cell. 2016 Sep 12; 2016 Sep 1. PMID: 27593162
- Zhou KC, Huang BK, Gamm UA, Bhandari V, Khokha MK, Choma MA: Erratum: Particle streak velocimetry-optical coherence tomography: a novel method for multidimensional imaging of microscale fluid flows: erratum. Biomed Opt Express. 2016 Jun 1; 2016 May 23. PMID: 27375950
- Zhou KC, Huang BK, Gamm UA, Bhandari V, Khokha MK, Choma MA: Particle streak velocimetry-optical coherence tomography: a novel method for multidimensional imaging of microscale fluid flows. Biomed Opt Express. 2016 Apr 1; 2016 Mar 30. PMID: 27375926
- Duncan AR, Khokha MK: Xenopus as a model organism for birth defects-Congenital heart disease and heterotaxy. Semin Cell Dev Biol. 2016 Mar; 2016 Feb 22. PMID: 26910255
- Owens NDL, Blitz IL, Lane MA, Patrushev I, Overton JD, Gilchrist MJ, Cho KWY, Khokha MK: Measuring Absolute RNA Copy Numbers at High Temporal Resolution Reveals Transcriptome Kinetics in Development. Cell Rep. 2016 Jan 26; 2016 Jan 7. PMID: 26774488
- Reza N, Khokha MK, Del Viso F: Nucleoporin gene expression in Xenopus tropicalis embryonic development. Int J Dev Biol. 2016. PMID: 27389988
- Bhattacharya D, Marfo CA, Li D, Lane M, Khokha MK: CRISPR/Cas9: An inexpensive, efficient loss of function tool to screen human disease genes in Xenopus. Dev Biol. 2015 Dec 15; 2015 Nov 4. PMID: 26546975
- Endicott SJ, Basu B, Khokha M, Brueckner M: The NIMA-like kinase Nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetry. Development. 2015 Dec 1; 2015 Oct 22. PMID: 26493400
- Moreno-Mateos MA, Vejnar CE, Beaudoin JD, Fernandez JP, Mis EK, Khokha MK, Giraldez AJ: CRISPRscan: designing highly efficient sgRNAs for CRISPR-Cas9 targeting in vivo. Nat Methods. 2015 Oct; 2015 Aug 31. PMID: 26322839
- Huang BK, Gamm UA, Bhandari V, Khokha MK, Choma MA: Three-dimensional, three-vector-component velocimetry of cilia-driven fluid flow using correlation-based approaches in optical coherence tomography. Biomed Opt Express. 2015 Sep 1; 2015 Aug 24. PMID: 26417520
- Griffin JN, Sondalle SB, Del Viso F, Baserga SJ, Khokha MK: The ribosome biogenesis factor Nol11 is required for optimal rDNA transcription and craniofacial development in Xenopus. PLoS Genet. 2015 Mar; 2015 Mar 10. PMID: 25756904
- Huang BK, Gamm UA, Jonas S, Khokha MK, Choma MA: Quantitative optical coherence tomography imaging of intermediate flow defect phenotypes in ciliary physiology and pathophysiology. J Biomed Opt. 2015 Mar. PMID: 25751026
- Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, Overton J, Meffre E, Khokha MK, Huttner AJ, West B, Podoltsev NA, Boggon TJ, Kazmierczak BI, Lifton RP: Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet. 2014 Oct; 2014 Sep 14. PMID: 25217960
- Boskovski MT, Yuan S, Pedersen NB, Goth CK, Makova S, Clausen H, Brueckner M, Khokha MK: The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality. Nature. 2013 Dec 19; 2013 Nov 13. PMID: 24226769
- Jonas S, Zhou E, Deniz E, Huang B, Chandrasekera K, Bhattacharya D, Wu Y, Fan R, Deserno TM, Khokha MK, Choma MA: A novel approach to quantifying ciliary physiology: microfluidic mixing driven by a ciliated biological surface. Lab Chip. 2013 Nov 7. PMID: 23970350
- Lane MA, Kimber M, Khokha MK: Breeding based remobilization of Tol2 transposon in Xenopus tropicalis. PLoS One. 2013; 2013 Oct 8. PMID: 24116167
- van Veenendaal NR, Ulmer B, Boskovski MT, Fang X, Khokha MK, Wendler CC, Blum M, Rivkees SA: Embryonic exposure to propylthiouracil disrupts left-right patterning in Xenopus embryos. FASEB J. 2013 Feb; 2012 Nov 12. PMID: 23150524
- del Viso F, Bhattacharya D, Kong Y, Gilchrist MJ, Khokha MK: Exon capture and bulk segregant analysis: rapid discovery of causative mutations using high-throughput sequencing. BMC Genomics. 2012 Nov 21; 2012 Nov 21. PMID: 23171430
- Deniz E, Jonas S, Khokha M, Choma MA: Endogenous contrast blood flow imaging in embryonic hearts using hemoglobin contrast subtraction angiography. Opt Lett. 2012 Jul 15. PMID: 22825198
- Khokha MK: Xenopus white papers and resources: folding functional genomics and genetics into the frog. Genesis. 2012 Mar; 2012 Feb 20. PMID: 22287484
- del Viso F, Khokha M: Generating diploid embryos from Xenopus tropicalis. Methods Mol Biol. 2012. PMID: 22956081
- Fakhro KA, Choi M, Ware SM, Belmont JW, Towbin JA, Lifton RP, Khokha MK, Brueckner M: Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. Proc Natl Acad Sci U S A. 2011 Feb 15; 2011 Jan 31. PMID: 21282601
- Khokha MK, Krylov V, Reilly MJ, Gall JG, Bhattacharya D, Cheung CY, Kaufman S, Lam DK, Macha J, Ngo C, Prakash N, Schmidt P, Tlapakova T, Trivedi T, Tumova L, Abu-Daya A, Geach T, Vendrell E, Ironfield H, Sinzelle L, Sater AK, Wells DE, Harland RM, Zimmerman LB: Rapid gynogenetic mapping of Xenopus tropicalis mutations to chromosomes. Dev Dyn. 2009 Jun. PMID: 19441086