Professional Education

  • Doctor of Philosophy, Vanderbilt University (2023)

Stanford Advisors

All Publications

  • Fragile X mental retardation protein coordinates neuron-to-glia communication for clearance of developmentally transient brain neurons. Proceedings of the National Academy of Sciences of the United States of America Song, C., Broadie, K. 2023; 120 (12): e2216887120


    In the developmental remodeling of brain circuits, neurons are removed by glial phagocytosis to optimize adult behavior. Fragile X mental retardation protein (FMRP) regulates neuron-to-glia signaling to drive glial phagocytosis for targeted neuron pruning. We find that FMRP acts in a mothers against decapentaplegic (Mad)-insulin receptor (InR)-protein kinase B (Akt) pathway to regulate pretaporter (Prtp) and amyloid precursor protein-like (APPL) signals directing this glial clearance. Neuronal RNAi of Drosophila fragile X mental retardation 1 (dfmr1) elevates mad transcript levels and increases pMad signaling. Neuronal dfmr1 and mad RNAi both elevate phospho-protein kinase B (pAkt) and delay neuron removal but cause opposite effects on InR expression. Genetically correcting pAkt levels in the mad RNAi background restores normal remodeling. Consistently, neuronal dfmr1 and mad RNAi both decrease Prtp levels, whereas neuronal InR and akt RNAi increase Prtp levels, indicating FMRP works with pMad and insulin signaling to tightly regulate Prtp signaling and thus control glial phagocytosis for correct circuit remodeling. Neuronal dfmr1 and mad and akt RNAi all decrease APPL levels, with the pathway signaling higher glial endolysosome activity for phagocytosis. These findings reveal a FMRP-dependent control pathway for neuron-to-glia communication in neuronal pruning, identifying potential molecular mechanisms for devising fragile X syndrome treatments.

    View details for DOI 10.1073/pnas.2216887120

    View details for PubMedID 36920921

  • FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission PLOS BIOLOGY Leahy, S. N., Song, C., Vita, D. J., Broadie, K. 2023; 21 (1): e3001969


    Noonan syndrome (NS) and NS with multiple lentigines (NSML) cognitive dysfunction are linked to SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) gain-of-function (GoF) and loss-of-function (LoF), respectively. In Drosophila disease models, we find both SHP2 mutations from human patients and corkscrew (csw) homolog LoF/GoF elevate glutamatergic transmission. Cell-targeted RNAi and neurotransmitter release analyses reveal a presynaptic requirement. Consistently, all mutants exhibit reduced synaptic depression during high-frequency stimulation. Both LoF and GoF mutants also show impaired synaptic plasticity, including reduced facilitation, augmentation, and post-tetanic potentiation. NS/NSML diseases are characterized by elevated MAPK/ERK signaling, and drugs suppressing this signaling restore normal neurotransmission in mutants. Fragile X syndrome (FXS) is likewise characterized by elevated MAPK/ERK signaling. Fragile X Mental Retardation Protein (FMRP) binds csw mRNA and neuronal Csw protein is elevated in Drosophila fragile X mental retardation 1 (dfmr1) nulls. Moreover, phosphorylated ERK (pERK) is increased in dfmr1 and csw null presynaptic boutons. We find presynaptic pERK activation in response to stimulation is reduced in dfmr1 and csw nulls. Trans-heterozygous csw/+; dfmr1/+ recapitulate elevated presynaptic pERK activation and function, showing FMRP and Csw/SHP2 act within the same signaling pathway. Thus, a FMRP and SHP2 MAPK/ERK regulative mechanism controls basal and activity-dependent neurotransmission strength.

    View details for DOI 10.1371/journal.pbio.3001969

    View details for Web of Science ID 000955081300001

    View details for PubMedID 36701299

    View details for PubMedCentralID PMC9879533

  • Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome. Frontiers in cell and developmental biology Song, C., Broadie, K. 2022; 10: 934662


    Drosophila models of neurological disease contribute tremendously to research progress due to the high conservation of human disease genes, the powerful and sophisticated genetic toolkit, and the rapid generation time. Fragile X syndrome (FXS) is the most prevalent heritable cause of intellectual disability and autism spectrum disorders, and the Drosophila FXS disease model has been critical for the genetic screening discovery of new intercellular secretion mechanisms. Here, we focus on the roles of three major signaling pathways: BMP, Wnt, and insulin-like peptides. We present Drosophila FXS model defects compared to mouse models in stem cells/embryos, the glutamatergic neuromuscular junction (NMJ) synapse model, and the developing adult brain. All three of these secreted signaling pathways are strikingly altered in FXS disease models, giving new mechanistic insights into impaired cellular outcomes and neurological phenotypes. Drosophila provides a powerful genetic screening platform to expand understanding of these secretory mechanisms and to test cellular roles in both peripheral and central nervous systems. The studies demonstrate the importance of exploring broad genetic interactions and unexpected regulatory mechanisms. We discuss a number of research avenues to pursue BMP, Wnt, and insulin signaling in future FXS investigations and the development of potential therapeutics.

    View details for DOI 10.3389/fcell.2022.934662

    View details for PubMedID 35880195

    View details for PubMedCentralID PMC9307498

  • RNA-binding FMRP and Staufen sequentially regulate the Coracle scaffold to control synaptic glutamate receptor and bouton development. Development (Cambridge, England) Song, C., Leahy, S. N., Rushton, E. M., Broadie, K. 2022; 149 (9)


    Both mRNA-binding Fragile X mental retardation protein (FMRP; Fmr1) and mRNA-binding Staufen regulate synaptic bouton formation and glutamate receptor (GluR) levels at the Drosophila neuromuscular junction (NMJ) glutamatergic synapse. Here, we tested whether these RNA-binding proteins act jointly in a common mechanism. We found that both dfmr1 and staufen mutants, and trans-heterozygous double mutants, displayed increased synaptic bouton formation and GluRIIA accumulation. With cell-targeted RNA interference, we showed a downstream Staufen role within postsynaptic muscle. With immunoprecipitation, we showed that FMRP binds staufen mRNA to stabilize postsynaptic transcripts. Staufen is known to target actin-binding, GluRIIA anchor Coracle, and we confirmed that Staufen binds to coracle mRNA. We found that FMRP and Staufen act sequentially to co-regulate postsynaptic Coracle expression, and showed that Coracle, in turn, controls GluRIIA levels and synaptic bouton development. Consistently, we found that dfmr1, staufen and coracle mutants elevate neurotransmission strength. We also identified that FMRP, Staufen and Coracle all suppress pMad activation, providing a trans-synaptic signaling linkage between postsynaptic GluRIIA levels and presynaptic bouton development. This work supports an FMRP-Staufen-Coracle-GluRIIA-pMad pathway regulating structural and functional synapse development.

    View details for DOI 10.1242/dev.200045

    View details for PubMedID 35394012

    View details for PubMedCentralID PMC9148565