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Left-Right Patterning in the Vertebrate Embryo
In my laboratory we are using the zebrafish to study how the left-right (LR) axis and pattern is established. Vertebrates appear bilaterally symmetric, but have internal asymmetries along the LR axis. This axis is revealed by the asymmetric placement of organs along the midline. For example, the human heart is located on the left of the body cavity, while the liver is located on the right. While genes implicated in LR patterning have been identified, we do not know how the LR axis is established, how the axis is aligned with the existing dorsal-ventral and anterior-posterior axes, or how LR information is received and interpreted by developing organs. Proper LR axis formation is critical for organogenesis as correct organ placement allows for proper connectivity with the developing vasculature. In humans, defects in LR patterning often manifest as congenital heart disease. Our current studies focus on a pathway known to be involved in left-right patterning, and on identifying new genes involved in this process.
The role of Nodal signaling in left-right patterning
In all vertebrates, components of the Nodal signaling pathway are expressed asymmetrically in the left lateral plate mesoderm, a tissue that will give rise to many asymmetric visceral organs. These components include the nodal ligand, the feedback inhibitor lefty, and the downstream transcription factor pitx2. In zebrafish we have an additional asymmetric expression domain for these genes in the developing brain. We are using zebrafish one-eyed pinhead (oep) mutants to explore the role of Nodal signaling in LR patterning of the viscera and brain. Oep is a member of the EGF-CFC family of proteins, which act as co-factors that are absolutely required for Nodal signaling. In oep mutants, asymmetric organs in the viscera and brain are still asymmetrically placed, but their positioning is randomized compared to wild-type controls. For example, the pancreas is correctly positioned on the right in approximately half of oep embryos, and on the left in the other half. This suggests Nodal is not required to generate asymmetries, but is required to properly direct their asymmetric position such that a consistent pattern is achieved. Future work in the lab will focus on when and where the Nodal signaling pathway is required for proper LR patterning and how this pathway provides directional information to developing organs.
Understanding how organs obtain asymmetric positions
How an organ obtains its final asymmetric position is not understood. Organs such as the heart and pancreas form in the midline, and obtain asymmetric positions later in development. To examine the cell movements that occur during this process, we are taking advantage of the transparency of zebrafish embryos. We are using GFP transgenics to observe cell behaviors during organ morphogenesis in the living embryo. To complement this descriptive approach, we are studying new zebrafish mutants to identify additional genes that affect LR organ patterning. In Class I mutants, organs that are normally asymmetric remain in midline positions. The identification of the genes affected in these mutants will further our understanding of how organs are asymmetrically positioned. Class II mutants have a complete reversal of asymmetric organs in half of the mutant embryos, and wild-type LR patterning in the other half. Class III mutants have randomized organ positioning similar to what is observed in oep mutants. Some of the Class III mutations have additional defects in the kidney. Cloning and characterizing the genes affected in these mutants will provide insights into how the embryos establishes and patterns the LR axis, and how these genes may be used in other contexts, such as kidney formation.
Selected Publications
Serluca FC, Xu B, Okabe N, Baker K, Lin SY, Sullivan-Brown J, Konieczkowski DJ, Jaffe KM, Bradner J, Fishman M, Burdine RD. (2009) Mutations in zebrafish leucine-rich repeat-containing six-like affect cilia motility, result in pronephric cysts, but have variable effects on left-right patterning. Development 136: 1621-1631. PubMed
Okabe N, Xu B, Burdine RD. (2008) Fluid dynamics in Zebrafish Kupffer's vesicle. Dev Dyn. 237: 3602-3612 PubMed
Baker K, Holtzman NG, Burdine RD. (2008) Direct and indirect roles for nodal signaling in rwo axis conversions during asymmetric morphogenesis of the Zebrafish heart. Proc Natl. Acad. Sci. 105: 13924-13929. PubMed
Weber S, Taylor JC, Winyard P, Baker KF, Sullivan-Brown J, Schild R, Knüppel T, Zurowska AM, Caldas-Alfonso A, Litwin M, Emre S, Ghiggeri GM, Bakkaloglu A, Mehls O, Antignac C, ESCAPE Network, Schaefer F, Burdine RD. (2008) SIX2 and BMP4 mutations associate with anomalous kidney development. J Amer Soc Nephr 19: 891-903. PubMed
Schoetz EM, Burdine RD, Jüelicher F, Steinberg MS, Heisenberg CP, Foty RA. (2008) Quantitative differences in tissue surface tension influence zebrafish germ layer positioning. HFSP Journal 2: 42-56. abstract
Sullivan-Brown J, Schottenfeld J, Okabe N, Hostetter CL, Serluca FC, Thiberge SY, Burdine RD. (2008) Zebrafish mutations affecting cilia motility share similar cystic phenotypes and suggest a mechanism of cyst formation that differs from pkd2 morphants. Dev Biol 314: 261-275. PubMed
Fan X, Hagos EG, Xu B, Sias C, Kawakami K, Burdine RD, Dougan ST. (2007) Nodal signals mediate interactions between the extra-embryonic and embryonic tissues in zebrafish. Dev Biol 310: 363-378. PubMed
Schottenfeld J, Sullivan-Brown J, Burdine RD. (2007) Zebrafish curly up encodes a pkd2 ortholog that restricts left-side-specific expression southpaw. Development 134, 1605-1615. PubMed
Lin SY, Burdine RD. (2005) Brain asymmetry: switching from left to right. Curr Biol 15: R343-345. PubMed
Dutta S, Dietrich JE, Aspock G, Burdine RD, Schier A, Westerfield M, Varga ZM. (2005) pitx3 defines an equivalence domain for lens and anterior pituitary placode. Development 132: 1579-1590. PubMed
Hostetter CL, Sullivan-Brown JL, Burdine RD. (2003) Zebrafish pronephros: a model for understanding cystic kidney disease. Dev Dyn 228: 514-522. PubMed
de la Cruz JM, Bamford RN, Burdine RD, Roessler E, Barkovich AJ, Donnai D, Schier AF, Muenke M. (2002) A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects. Hum Genet 110: 422-428. PubMed
Concha ML, Burdine RD, Russell C, Schier AF and Wilson SW. (2000) A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain. Neuron 28: 399-409. PubMed
Burdine RD, Schier AF. (2000) Conserved and divergent mechanisms in left-right axis formation. Genes Dev 14: 763-776. PubMed
Bamford RN, Roessler E, Burdine RD, Saplakoglu U, dela Cruz J, Splitt M, Goodship JA, Towbin J, Bowers P, Ferrero GB, Marino B, Schier AF, Shen MM, Muenke M, Casey B. (2000) Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet 26: 365-369. PubMed
Yan YT, Gritsman K, Ding J, Burdine RD, Corrales JD, Price SM, Talbot WS, Schier AF, Shen MM. (1999) Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. Genes Dev 13: 2527-2537. PubMed