2. Academic Validation
  3. Regionally defined proteomic profiles of human cerebral tissue and organoids reveal conserved molecular modules of neurodevelopment

Regionally defined proteomic profiles of human cerebral tissue and organoids reveal conserved molecular modules of neurodevelopment

  • Cell Rep. 2022 May 24;39(8):110846. doi: 10.1016/j.celrep.2022.110846.
Sofia Melliou 1,  Kevin T Sangster 2,  Jennifer Kao 3,  Mehdi Zarrei 4,  K H Brian Lam 1,  Jennifer Howe 4,  Michail-Dimitrios Papaioannou 2,  Queenie P L Tsang 2,  Okty Abbasi Borhani 2,  Rifat Shahriar Sajid 1,  Céline Bonnet 5,  Bruno Leheup 5,  Patrick Shannon 6,  Stephen W Scherer 7,  Dimitri James Stavropoulos 8,  Ugljesa Djuric 2,  Phedias Diamandis 9
Affiliations

Affiliations

  • 1 Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 2 Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 1L7, Canada.
  • 3 Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 4 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • 5 Department of Clinical Genetics, Nancy University Hospital, Nancy, France.
  • 6 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • 7 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, ON M5G 1X5, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • 8 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • 9 Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Laboratory Medicine Program, University Health Network, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].
PMID: 35613588 DOI: 10.1016/j.celrep.2022.110846
Abstract

Cerebral organoids have emerged as robust models for neurodevelopmental and pathological processes, as well as a powerful discovery platform for less-characterized neurobiological programs. Toward this prospect, we leverage mass-spectrometry-based proteomics to molecularly profile precursor and neuronal compartments of both human-derived organoids and mid-gestation fetal brain tissue to define overlapping programs. Our analysis includes recovery of precursor-enriched transcriptional regulatory proteins not found to be differentially expressed in previous transcriptomic datasets. To highlight the discovery potential of this resource, we show that RUVBL2 is preferentially expressed in the SOX2-positive compartment of organoids and that chemical inactivation leads to precursor cell displacement and Apoptosis. To explore clinicopathological correlates of this cytoarchitectural disruption, we interrogate clinical datasets and identify rare de novo genetic variants involving RUVBL2 in patients with neurodevelopmental impairments. Together, our findings demonstrate how cell-type-specific profiling of organoids can help nominate previously unappreciated genes in neurodevelopment and disease.

Keywords

CP: Neuroscience; cerebral organoids; mass spectrometry; neurodevelopment; proteomics.

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