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Principal Investigator: Erin Flaherty
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $131,733
Funding agency: National Institute of Mental Health
PROJECT SUMMARY
During development, individual neurons extend highly branched neurites that innervate the surrounding
territory with minimal overlap. In mammals, the clustered protocadherins (Pcdh) provide each neuron with a
unique cell specific identity required for self-identification and self-avoidance in the brain. Individual PCDHa/b/g
protein isoforms cis-dimerize, and engage in homophilic trans interactions to create a lattice-like structure at
contacting membrane surfaces, providing the diversity required for self-recognition. Deletion of Pcdh genes in
mice results in deficits in neuronal wiring and altered behaviors. Biophysical and structural data, cellular
assays, and functional studies support a model in which perfect homophilic matching of PCDH isoforms leads
to the assembly of an extended PCDH lattice structure on sister neurites, triggering intracellular signaling, and
a series of yet to be identified steps leading to self-avoidance. Many neuronal transmembrane proteins execute
neurodevelopmental processes through both nuclear and membrane associated signaling mechanisms;
however, the mechanisms regulating PCDH mediated self-avoidance remain unknown.
My recent work in the Maniatis lab has demonstrated that the PCDHa/g intracellular domain (ICDs) are
required for interactions with protein partners at the membrane (e.g. WAVE complex and WNT signaling
modulators) and in the nucleus (e.g. chromatin and transcriptional regulators). In the nucleus, the PCDH-ICD
interacts with and may regulate the expression of genes involved in axon guidance, synapse formation and
participate in an auto-regulatory feedback loop. During the K99 phase, I will leverage these preliminary findings
to assess the need for each downstream signaling mechanism for proper self-avoidance in vitro (Aim 1) and in
vivo (Aim 2). During the independent R00 phase, I will implement knowledge and techniques acquired in the
mentored phase to investigate whether PCDH SNVs from ASD cases disrupt the identified downstream
signaling mechanisms, proper self-avoidance and neural circuitry during development (Aim 3). Understanding
the mechanisms of self-avoidance is a fundamental step toward revealing how neural circuits are formed
during development in vertebrates and could have important implications for neurodevelopmental disorders.
The work described in the mentored portion of this proposal will be conducted under the mentorship of Dr.
Maniatis, who has a strong record of mentoring postdoctoral research scientists who have transitioned into
their own laboratories. Ultimately, this award will allow me to accomplish three broad training goals including;
(1) learning to address biological questions using in vivo models, (2) developing and extending my knowledge
of molecular and genetic approaches to probe gene function, and (3) expanding on my background in iPSC
based disease modeling by probing PCDH function in cortical organoids. Achieving these goals and training
will provide me with the strong foundation required to pursue a faculty position at a research institution where I
can integrate in vitro and in vivo approaches to investigate novel questions in the field of neurodevelopment.
Terms: <ASD><Actin Filaments><Address><Autism><Autistic Disorder><Award><Behavior><Biological><Biophysics><Brain><Brain Nervous System><Causality><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cell membrane><Cells><Cellular Assay><Chromatin><Complex><Cytoplasm><Cytoplasmic Membrane><Data><Development><Dimerization><Disease><Disorder><Early Infantile Autism><Encephalon><Etiology><Evaluation><Event><Faculty><Feedback><Foundations><G-Proteins><GTP-Binding Proteins><GTP-Regulatory Proteins><Gene Cluster><Gene Expression><Gene Transcription><Genes><Genetic><Genetic Transcription><Goals><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Human><In Vitro><Individual><Infantile Autism><Institution><Integral Membrane Protein><Intracellular Communication and Signaling><Intrinsic Membrane Protein><Isoforms><Kanner's Syndrome><Knowledge><Laboratories><Learning><Link><Lymphatic cell><Lymphocyte><Lymphocytic><Mammalia><Mammals><Mediating><Membrane><Mentors><Mentorship><Mice><Mice Mammals><Microfilaments><Modeling><Modern Man><Molecular><Movement><Murine><Mus><Myofilaments><Needs Assessment><Nerve Cells><Nerve Unit><Neural Cell><Neural Development><Neural Transmission><Neurites><Neurocyte><Neurodevelopmental Disorder><Neurological Development Disorder><Neurons><Nuclear><Nucleus><Organoids><Patients><Peptide Domain><Phase><Plasma Membrane><Position><Positioning Attribute><Postdoc><Postdoctoral Fellow><Process><Protein Dimerization><Protein Domains><Protein Isoforms><Proteins><RNA Expression><Research><Research Associate><Role><Schizophrenia><Schizophrenic Disorders><Scientist><Series><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single Base Polymorphism><Single Nucleotide Polymorphism><Sister><Structure><Surface><Synapses><Synaptic><Synaptic Transmission><Techniques><Tertiary Protein Structure><Testing><Training><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transmembrane Protein><Transmembrane Protein Gene><Variant><Variation><Vertebrate Animals><Vertebrates><WNT Signaling Pathway><WNT signaling><Work><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><axon growth cone guidance><axon guidance><biologic><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><body movement><causation><cell assay><dementia praecox><developmental><disease causation><disease model><disorder model><gene function><genetic approach><genetic strategy><iPS><iPSC><iPSCs><in vivo><in vivo Model><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><insight><lymph cell><membrane biogenesis><membrane structure><neural><neural circuit><neural circuitry><neurocircuitry><neurodevelopment><neurodevelopmental disease><neuronal><neuronal circuit><neuronal circuitry><neuropsychiatric disease><neuropsychiatric disorder><notch><notch protein><notch receptors><novel><plasmalemma><post-doc><post-doctoral><post-doctoral trainee><proband><protein function><research associates><schizophrenic><screening><screenings><single nucleotide variant><social role><synapse><synapse formation><synaptic circuit><synaptic circuitry><synaptogenesis><vertebrata>