Document text
Principal Investigator: Xiaoyan Zheng
Organization: GEORGE WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $19,230
Funding agency: National Institute of General Medical Sciences
Project summary/abstract
The establishment of left-right (LR) asymmetry is a critical event required for the correct positioning of internal
organs. Defects in human LR axis formation cause birth defects of the heart, vasculature, lungs, and intestinal
tract. The gene network contributing to the generation of LR asymmetry is highly conserved across
vertebrates. In the mouse, the initial asymmetric signals establishing LR axis are determined in the node by
cilia-driven leftward fluid flow (nodal flow). These signals are then transferred to the left lateral plate mesoderm
(LPM), which will undergo asymmetric organ morphogenesis. Nodal, a secretory protein that belongs to the
transforming growth factor-b (TGF-b) superfamily, is expressed in the node and travels a long distance to the
left LPM, where it initiates a transient auto-regulatory circuit (involving Nodal and Lefty) that propagates Nodal
signaling and activates expression of the left-sided determinant Paired-Like Homeodomain transcription
factor 2 (Pitx2). The Hedgehog (Hh) signaling pathway also plays a crucial role in LR patterning. In the mouse,
Hh signaling is required to establish the midline that separates the left and right sides of the embryo, as well as
to activate the Nodal-dependent auto-regulatory circuit in the LPM. However, the mechanism by which Hh
signaling regulates the competence of the LPM for Nodal response is not well understood. Thus, identifying the
specific convergence point of the Hh and TGF-b pathways is critical for understanding the in-depth mechanism
underlying LR asymmetry determination, and therefore to provide better diagnosis, preventive and therapeutic
intervention against
LR asymmetry-related birth defects.
We recently found that a novel target of the Hh pathway, Neuron-Derived Neurotrophic Factor (Ndnf),
regulates axial rotation and intestinal looping in the mouse. In the proposed work, we will incorporate
biochemical, molecular, and genetic approaches to (Aim 1) assess the source, (Aim 2) determine the
transcriptional regulation, and (Aim 3) investigate the underlying molecular mechanisms of Ndnf in LR
determination.
Terms: <Basal Transcription Factor><Basal transcription factor genes><Biochemical><Birth Defects><Bone-Derived Transforming Growth Factor><Cardiac defect><Cell Communication and Signaling><Cell Signaling><Cilia><Competence><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Defect><Diagnosis><Embryo><Embryonic><Erinaceidae><Event><General Transcription Factor Gene><General Transcription Factors><Generations><Hedgehogs><Homeo Domain><Human><Intestinal><Intestines><Intracellular Communication and Signaling><Lateral><Left><Link><Lung><Lung Respiratory System><Mediating><Mesoderm><Mice><Mice Mammals><Milk Growth Factor><Modern Man><Molecular><Morphogenesis><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nodal><Organ><Pathway interactions><Pattern><Platelet Transforming Growth Factor><Play><Position><Positioning Attribute><Preventative intervention><Regulation><Research><Role><Rotation><Side><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Source><Structure><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Therapeutic Intervention><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Transforming Growth Factors><Travel><Tumor Growth Factors><Vertebrate Animals><Vertebrates><Work><biological signal transduction><bowel><experiment><experimental research><experimental study><experiments><falls><fluid flow><gene network><genetic approach><genetic strategy><heart defect><homeodomain><intervention for prevention><intervention therapy><morphogenetic process><neuronal><neurotrophic factor><neurotrophin><neutrophin><novel><parent grant><pathway><prevention intervention><preventional intervention strategy><preventive intervention><pulmonary><response><secretory protein><social role><transcription factor><transforming growth factors Animal growth regulators><vertebrata>