Modeling Human Telencephalic Development and Autism-associated SHANK3 Deficiency Using Organoids Generated from Single Neural Rosettes

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Oct 6

PMID 36202854

Authors

Yueqi Wang

Simone Chiola

Guang Yang

Chad Russell

Celeste J Armstrong

Yuanyuan Wu

Jay Spampanato

Paisley Tarboton

H M Arif Ullah

Nicolas U Edgar

Amelia N Chang

David A Harmin

Vittoria Dickinson Bocchi

Elena Vezzoli

Dario Besusso

Jun Cui

Elena Cattaneo

Jan Kubanek

Aleksandr Shcheglovitov

Affiliations

Soon will be listed here.

Abstract

Human telencephalon is an evolutionarily advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remain largely unknown. We produce human telencephalic organoids from stem cell-derived single neural rosettes and investigate telencephalic development under normal and pathological conditions. We show that single neural rosette-derived organoids contain pallial and subpallial neural progenitors, excitatory and inhibitory neurons, as well as macroglial and periendothelial cells, and exhibit predictable organization and cytoarchitecture. We comprehensively characterize the properties of neurons in SNR-derived organoids and identify transcriptional programs associated with the specification of excitatory and inhibitory neural lineages from a common pool of NPs early in telencephalic development. We also demonstrate that neurons in organoids with a hemizygous deletion of an autism- and intellectual disability-associated gene SHANK3 exhibit intrinsic and excitatory synaptic deficits and impaired expression of several clustered protocadherins. Collectively, this study validates SNR-derived organoids as a reliable model for studying human telencephalic cortico-striatal development and identifies intrinsic, synaptic, and clustered protocadherin expression deficits in human telencephalic tissue with SHANK3 hemizygosity.

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