The consistent left-right (LR) asymmetry of the vertebrate bodyplan is a fascinating puzzle of developmental and evolutionary biology, and has profound implications for biomedicine. Laterality defects affect more than 1 in 6000 babies born to term, and the molecular details are crucial to understanding, detection, prevention, and repair of birth defects related to errors of LR patterning. The field is currently in disarray, lacking conceptual models that can link mechanisms uncovered for the LR patterning of mouse and zebrafish embryos to the much earlier mechanisms that have been discovered in Xenopus. Our recent work has identified completely novel ion flow-dependent events that function in early LR patterning and are conserved to frog, chick, and zebrafish. However, the existing models do not explain how voltage gradients can be reliably oriented with respect to the LR axis in chick and mammalian body-plans. Exciting data indicate that endogenous voltage and pH gradients produced by ion channel and pump-dependent current flows in cells and tissues regulate a number of important morphogenetic events in embryonic development and regeneration. The recent explosion of work focused on gene transcription networks and secreted signaling factors have largely neglected these fascinating epigenetic biophysical phenomena. Our lab combines the powerful modern tools of molecular and cell biology, biophysics, physiology, and computer modeling; thus, our work will not only contribute to understanding left-right patterning but also reveal new molecular details of how endogenous ion flows control cell behavior. Our approaches and reagents present a valuable and unique opportunity to resolve the major puzzle of how early, cytoplasmic events that set up asymmetry in large blastomeres aligned with the embryo's midline may function in other animals (such as mammals) where many small cells exist instead. We will resolve this puzzle by addressing the major outstanding questions through (1) determining how 3 specific ion transporters are involved in the imposition of LR asymmetry onto large cell fields by foci of autonomous """"""""organizers"""""""", and (2) characterizing the interaction of polarity and cytoskeleton proteins in controlling the localization and/or behavior of ion fluxes in cells. Together, these experiments take advantage of a powerful set of approaches in a model system (Xenopus) amenable to both molecular genetics and functional biophysics. By capitalizing on the exciting base of preliminary and published data that we have obtained, our work will reveal novel mechanisms that can be used to gain insight into the cell and evolutionary biology of morphogenesis, will integrate this field with mainstream molecular developmental biology, and will ultimately serve as the basis for novel approaches targeting many areas of birth defects, regeneration, and tumor biology. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM077425-01A2
Application #
7319817
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Haynes, Susan R
Project Start
2007-08-01
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$312,064
Indirect Cost
Name
Forsyth Institute
Department
Type
DUNS #
062190616
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Vandenberg, Laura N; Blackiston, Douglas J; Rea, Adam C et al. (2014) Left-right patterning in Xenopus conjoined twin embryos requires serotonin signaling and gap junctions. Int J Dev Biol 58:799-809
Hernández-Díaz, Sonia; Levin, Michael (2014) Alteration of bioelectrically-controlled processes in the embryo: a teratogenic mechanism for anticonvulsants. Reprod Toxicol 47:111-4
Rea, Adam C; Vandenberg, Laura N; Ball, Rebecca E et al. (2013) Light-activated serotonin for exploring its action in biological systems. Chem Biol 20:1536-46
Vandenberg, Laura N; Morrie, Ryan D; Seebohm, Guiscard et al. (2013) Rab GTPases are required for early orientation of the left-right axis in Xenopus. Mech Dev 130:254-71
Vandenberg, Laura N; Lemire, Joan M; Levin, Michael (2013) Serotonin has early, cilia-independent roles in Xenopus left-right patterning. Dis Model Mech 6:261-8
Vandenberg, Laura N; Levin, Michael (2013) A unified model for left-right asymmetry? Comparison and synthesis of molecular models of embryonic laterality. Dev Biol 379:1-15
Levin, Michael (2013) Reprogramming cells and tissue patterning via bioelectrical pathways: molecular mechanisms and biomedical opportunities. Wiley Interdiscip Rev Syst Biol Med 5:657-76
Vandenberg, Laura N; Lemire, Joan M; Levin, Michael (2013) It's never too early to get it Right: A conserved role for the cytoskeleton in left-right asymmetry. Commun Integr Biol 6:e27155
Blackiston, Douglas J; Levin, Michael (2013) Inversion of left-right asymmetry alters performance of Xenopus tadpoles in nonlateralized cognitive tasks. Anim Behav 86:459-466
Lobikin, Maria; Wang, Gang; Xu, Jingsong et al. (2012) Early, nonciliary role for microtubule proteins in left-right patterning is conserved across kingdoms. Proc Natl Acad Sci U S A 109:12586-91

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