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Germline PTEN genotype-dependent phenotypic divergence during the early neural developmental process of forebrain organoids

Molecular Psychiatry (2023)Cite this article

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Abstract

PTEN germline mutations account for ~0.2–1% of all autism spectrum disorder (ASD) cases, as well as ~17% of ASD patients with macrocephaly, making it one of the top ASD-associated risk genes. Individuals with germline PTEN mutations receive the molecular diagnosis of PTEN Hamartoma Tumor Syndrome (PHTS), an inherited cancer predisposition syndrome, about 20–23% of whom are diagnosed with ASD. We generated forebrain organoid cultures from gene-edited isogenic human induced pluripotent stem cells (hiPSCs) harboring a PTENG132D (ASD) or PTENM134R (cancer) mutant allele to model how these mutations interrupt neurodevelopmental processes. Here, we show that the PTENG132D allele disrupts early neuroectoderm formation during the first several days of organoid generation, and results in deficient electrophysiology. While organoids generated from PTENM134R hiPSCs remained morphologically similar to wild-type organoids during this early stage in development, we observed disrupted neuronal differentiation, radial glia positioning, and cortical layering in both PTEN-mutant organoids at the later stage of 72+ days of development. Perifosine, an AKT inhibitor, reduced over-activated AKT and partially corrected the abnormalities in cellular organization observed in PTENG132D organoids. Single cell RNAseq analyses on early-stage organoids revealed that genes related to neural cell fate were decreased in PTENG132D mutant organoids, and AKT inhibition was capable of upregulating gene signatures related to neuronal cell fate and CNS maturation pathways. These findings demonstrate that different PTEN missense mutations can have a profound impact on neurodevelopment at diverse stages which in turn may predispose PHTS individuals to ASD. Further study will shed light on ways to mitigate pathological impact of PTEN mutants on neurodevelopment by stage-specific manipulation of downstream PTEN signaling components.

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Fig. 1: Forebrain organoid culture recapitulates human brain development.
Fig. 2: Morphological defects in cellular organization and patterning observed in mutant PTEN corticogenesis unit.
Fig. 3: Neuronal maturation is impaired in ASD-associated PTENG132D/WT organoids and delayed maturation of PTENG132D/WT brain organoid compared to PTENWT/WT and PTENM134R/WT.
Fig. 4: VZ-like lumen morphology and radial glial patterning are disrupted during early development as well as activated AKT signaling in early mutant PTEN organoid development.
Fig. 5: PAKT regulates lumen morphology and neuroepithelial cell alignment in PTENG132D/WT organoids.

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Data availability

Raw count matrix used for scRNAseq analysis is available in Supplementary Table 7.

Code availability

The present study applied previously published approaches, of which codes are shared on public repositories: Seurat (https://github.com/satijalab/seurat), Monocle3 (https://github.com/cole-trapnell-lab/monocle3).

References

  1. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Arlington, VA: American Psychiatric Publishing; 2013.

  2. Lewis MH, Bodfish JW. Repetitive behavior disorders in autism. Ment Retard Dev D R. 1998;4:80–9.

    Article  Google Scholar 

  3. Bodfish JW, Symons FJ, Parker DE, Lewis MH. Varieties of repetitive behavior in autism: comparisons to mental retardation. J Autism Dev Disord. 2000;30:237–43.

    Article  CAS  PubMed  Google Scholar 

  4. Mahoney WJ. The aggressive and impulsive child: Innovations in assessment and treatment - a commentary. Paediatr Child Health. 2004;9:537–8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Esbensen AJ, Seltzer MM, Lam KS, Bodfish JW. Age-related differences in restricted repetitive behaviors in autism spectrum disorders. J Autism Dev Disord. 2009;39:57–66.

    Article  PubMed  Google Scholar 

  6. Minshew NJ, Williams DL. The new neurobiology of autism: cortex, connectivity, and neuronal organization. Arch Neurol. 2007;64:945–50.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Tilot AK, Frazier TW 2nd, Eng C. Balancing proliferation and connectivity in PTEN-associated autism spectrum disorder. Neurotherapeutics. 2015;12:609–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fetit R, Hillary RF, Price DJ, Lawrie SM. The neuropathology of autism: a systematic review of post-mortem studies of autism and related disorders. Neurosci Biobehav R. 2021;129:35–62.

    Article  Google Scholar 

  9. Paulsen B, Velasco S, Kedaigle A, Pigoni M, Quadrato G, Deo A. et al. Human brain organoids reveal accelerated development of cortical neuron classes as a shared feature of autism risk genes. Preprint at bioRxiv https://doi.org/10.1101/2020.11.10.376509 2020.

  10. Zeidan-Chulia F, Salmina AB, Malinovskaya NA, Noda M, Verkhratsky A, Moreira JC. The glial perspective of autism spectrum disorders. Neurosci Biobehav Rev. 2014;38:160–72.

    Article  PubMed  Google Scholar 

  11. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18:400–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Buxbaum JD, Cai G, Chaste P, Nygren G, Goldsmith J, Reichert J, et al. Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:484–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet. 2005;42:318–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McBride KL, Varga EA, Pastore MT, Prior TW, Manickam K, Atkin JF, et al. Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly. Autism Res. 2010;3:137–41.

    Article  PubMed  Google Scholar 

  15. Varga V, Losonczy A, Zemelman BV, Borhegyi Z, Nyiri G, Domonkos A, et al. Fast synaptic subcortical control of hippocampal circuits. Science. 2009;326:449–53.

    Article  CAS  PubMed  Google Scholar 

  16. O’Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science. 2012;338:1619–22.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Fu JM, Satterstrom FK, Peng M, Brand H, Collins RL, Dong S, et al. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat Genet. 2022;54:1320–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Simons Fundation Autism Research Initiative (SFARI). 2023. https://gene.sfari.org/database/human-gene/

  19. Lee H, Thacker S, Sarn N, Dutta R, Eng C. Constitutional mislocalization of Pten drives precocious maturation in oligodendrocytes and aberrant myelination in model of autism spectrum disorder. Transl Psychiatry. 2019;9:13.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kathuria A, Lopez-Lengowski K, Jagtap SS, McPhie D, Perlis RH, Cohen BM, et al. Transcriptomic landscape and functional characterization of induced pluripotent stem cell-derived cerebral organoids in schizophrenia. JAMA Psychiatry. 2020;77:745–54.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Shou Y, Liang F, Xu S, Li X. The application of brain organoids: from neuronal development to neurological diseases. Front Cell Dev Biol. 2020;8:579659.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lancaster MA, Knoblich JA. Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc. 2014;9:2329–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bershteyn M, Nowakowski TJ, Pollen AA, Di Lullo E, Nene A, Wynshaw-Boris A, et al. Human iPSC-derived cerebral organoids model cellular features of lissencephaly and reveal prolonged mitosis of outer radial glia. Cell Stem Cell. 2017;20:435–49.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Di Lullo E, Kriegstein AR. The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci. 2017;18:573–84.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373–9.

    Article  CAS  PubMed  Google Scholar 

  26. Tiscornia G, Vivas EL, Izpisua, Belmonte JC. Diseases in a dish: modeling human genetic disorders using induced pluripotent cells. Nat Med. 2011;17:1570–6.

    Article  CAS  PubMed  Google Scholar 

  27. Soldner F, Jaenisch R. Medicine. iPSC disease modeling. Science. 2012;338:1155–6.

    Article  PubMed  Google Scholar 

  28. Bock DD, Lee WC, Kerlin AM, Andermann ML, Hood G, Wetzel AW, et al. Network anatomy and in vivo physiology of visual cortical neurons. Nature. 2011;471:177–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kim DS, Ross PJ, Zaslavsky K, Ellis J. Optimizing neuronal differentiation from induced pluripotent stem cells to model ASD. Front Cell Neurosci. 2014;8:109.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C, et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell. 2016;165:1238–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Qian X, Jacob F, Song MM, Nguyen HN, Song H, Ming GL. Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat Protoc. 2018;13:565–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Adhya D, Swarup V, Nagy R, Dutan L, Shum C, Valencia-Alarcon EP, et al. Atypical neurogenesis in induced pluripotent stem cells from autistic individuals. Biol Psychiatry. 2021;89:486–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chan WK, Griffiths R, Price DJ, Mason JO. Cerebral organoids as tools to identify the developmental roots of autism. Mol Autism. 2020;11:58.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Leslie NR, Batty IH, Maccario H, Davidson L, Downes CP. Understanding PTEN regulation: PIP2, polarity and protein stability. Oncogene. 2008;27:5464–76.

    Article  CAS  PubMed  Google Scholar 

  35. Sanchez-Alegria K, Flores-Leon M, Avila-Munoz E, Rodriguez-Corona N, Arias C. PI3K signaling in neurons: a central node for the control of multiple functions. Int J Mol Sci. 2018;19:3725.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Vanderplow AM, Eagle AL, Kermath BA, Bjornson KJ, Robison AJ, Cahill ME. Akt-mTOR hypoactivity in bipolar disorder gives rise to cognitive impairments associated with altered neuronal structure and function. Neuron. 2021;109:1479–96.e1476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen YH, Pruett-Miller SM. Improving single-cell cloning workflow for gene editing in human pluripotent stem cells. Stem Cell Res. 2018;31:186–92.

    Article  CAS  PubMed  Google Scholar 

  38. Hitomi M, Stacey DW. The checkpoint kinase ATM protects against stress-induced elevation of cyclin D1 and potential cell death in neurons. Cytom A. 2010;77:524–33.

    Article  Google Scholar 

  39. Kang SC, Jaini R, Hitomi M, Lee H, Sarn N, Thacker S, et al. Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation. Mol Autism. 2020;11:43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hao Y, Hao S, Andersen-Nissen E, Mauck WM, Zheng S, Butler A, et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184:3573–87.e29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cao J, Spielmann M, Qiu X, Huang X, Ibrahim DM, Hill AJ, et al. The single-cell transcriptional landscape of mammalian organogenesis. Nature. 2019;566:496–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Qiu X, Mao Q, Tang Y, Wang L, Chawla R, Pliner HA, et al. Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017;14:979–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Trapnell C, Cacchiarelli D, Grimsby J, Pokharel P, Li S, Morse M, et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol. 2014;32:381–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Howard BM, Zhicheng M, Filipovic R, Moore AR, Antic SD, Zecevic N. Radial glia cells in the developing human brain. Neuroscientist. 2008;14:459–73.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Lopez-Tobon A, Villa CE, Cheroni C, Trattaro S, Caporale N, Conforti P, et al. Human cortical organoids expose a differential function of GSK3 on cortical neurogenesis. Stem Cell Rep. 2019;13:847–61.

    Article  CAS  Google Scholar 

  46. Kalebic N, Gilardi C, Stepien B, Wilsch-Brauninger M, Long KR, Namba T, et al. Neocortical expansion due to increased proliferation of basal progenitors is linked to changes in their morphology. Cell Stem Cell. 2019;24:535-50.

    Article  Google Scholar 

  47. Tischfield MA, Baris HN, Wu C, Rudolph G, Van Maldergem L, He W, et al. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell. 2010;140:74–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lui JH, Hansen DV, Kriegstein AR. Development and evolution of the human neocortex. Cell. 2011;146:18–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Beattie R, Hippenmeyer S. Mechanisms of radial glia progenitor cell lineage progression. FEBS Lett. 2017;591:3993–4008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Grego-Bessa J, Bloomekatz J, Castel P, Omelchenko T, Baselga J, Anderson KV. The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium. eLife. 2016;5:e12034.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Hribkova H, Grabiec M, Klemova D, Slaninova I, Sun YM. Calcium signaling mediates five types of cell morphological changes to form neural rosettes. J Cell Sci. 2018;131:jcs206896.

    PubMed  Google Scholar 

  52. Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128:157–70.

    Article  CAS  PubMed  Google Scholar 

  53. Paez J, Sellers WR. PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling. Cancer Treat Res. 2003;115:145–67.

    Article  CAS  PubMed  Google Scholar 

  54. He X, Saji M, Radhakrishnan D, Romigh T, Ngeow J, Yu Q, et al. PTEN lipid phosphatase activity and proper subcellular localization are necessary and sufficient for down-regulating AKT phosphorylation in the nucleus in Cowden syndrome. J Clin Endocrinol Metab. 2012;97:E2179–2187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Fournier MV, Fata JE, Martin KJ, Yaswen P, Bissell MJ. Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells. Cancer Res. 2009;69:4545–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mighell TL, Thacker S, Fombonne E, Eng C, O’Roak BJ. An integrated deep-mutational-scanning approach provides clinical insights on PTEN genotype-phenotype relationships. Am J Hum Genet. 2020;106:818–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Matreyek KA, Stephany JJ, Ahler E, Fowler DM. Integrating thousands of PTEN variant activity and abundance measurements reveals variant subgroups and new dominant negatives in cancers. Genome Med. 2021;13:165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Larue L, Ohsugi M, Hirchenhain J, Kemler R. E-cadherin null mutant embryos fail to form a trophectoderm epithelium. Proc Natl Acad Sci USA. 1994;91:8263–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat Genet. 1998;19:348–55.

    Article  PubMed  Google Scholar 

  60. Wang W, Lu G, Su X, Tang C, Li H, Xiong Z, et al. Pten-mediated Gsk3beta modulates the naive pluripotency maintenance in embryonic stem cells. Cell Death Dis. 2020;11:107.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Paulsen B, Velasco S, Kedaigle AJ, Pigoni M, Quadrato G, Deo AJ, et al. Autism genes converge on asynchronous development of shared neuron classes. Nature. 2022;602:268–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sullivan JM, De Rubeis S, Schaefer A. Convergence of spectrums: neuronal gene network states in autism spectrum disorder. Curr Opin Neurobiol. 2019;59:102–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Li Y, Muffat J, Omer A, Bosch I, Lancaster MA, Sur M, et al. Induction of expansion and folding in human cerebral organoids. Cell Stem Cell. 2017;20:385–396.e3.

    Article  PubMed  Google Scholar 

  64. Hermida MA, Dinesh Kumar J, Leslie NR. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. Adv Biol Regul. 2017;65:5–15.

    Article  CAS  PubMed  Google Scholar 

  65. Leung AW, Murdoch B, Salem AF, Prasad MS, Gomez GA, Garcia-Castro MI. WNT/beta-catenin signaling mediates human neural crest induction via a pre-neural border intermediate. Development. 2016;143:398–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhang G, Lübke L, Chen F, Beil T, Takamiya M, Diotel N, et al. Neuron-radial glial cell communication via BMP/Id1 signaling is key to long-term maintenance of the regenerative capacity of the adult zebrafish telencephalon. Cells. 2021;10:2794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Insall RH, Weiner OD. PIP3, PIP2, and cell movement-similar messages, different meanings? Dev Cell. 2001;1:743–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Thapa N, Anderson RA. PIP2 signaling, an integrator of cell polarity and vesicle trafficking in directionally migrating cells. Cell Adh Migr. 2012;6:409–12.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Wu H, Feng W, Chen J, Chan LN, Huang SY, Zhang MJ. PDZ domains of Par-3 as potential phosphoinositide signaling integrators. Mol Cell. 2007;28:886–98.

    Article  CAS  PubMed  Google Scholar 

  70. Planchon SM, Waite KA, Eng C. The nuclear affairs of PTEN. J Cell Sci. 2008;121:249–53.

    Article  CAS  PubMed  Google Scholar 

  71. Giandomenico SL, Sutcliffe M, Lancaster MA. Generation and long-term culture of advanced cerebral organoids for studying later stages of neural development. Nat Protoc. 2021;16:579–602.

    Article  CAS  PubMed  Google Scholar 

  72. Qian X, Su Y, Adam CD, Deutschmann AU, Pather SR, Goldberg EM, et al. Sliced human cortical organoids for modeling distinct cortical layer formation. Cell Stem Cell. 2020;26:766–81.e769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sarn N, Thacker S, Lee H, Eng C. Germline nuclear-predominant Pten murine model exhibits impaired social and perseverative behavior, microglial activation, and increased oxytocinergic activity. Mol Autism. 2021;12:41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Sarn N, Jaini R, Thacker S, Lee H, Dutta R, Eng C. Cytoplasmic-predominant Pten increases microglial activation and synaptic pruning in a murine model with autism-like phenotype. Mol Psychiatry. 2021;26:1458–71.

    Article  CAS  PubMed  Google Scholar 

  75. Poyhonen S, Er S, Domanskyi A, Airavaara M. Effects of neurotrophic factors in glial cells in the central nervous system: expression and properties in neurodegeneration and injury. Front Physiol. 2019;10:486.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Yehia L, Keel E, Eng C. The clinical spectrum of PTEN mutations. Annu Rev Med. 2020;71:103–16.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was funded in part by the Ambrose Monell PTEN Switch grant (to CE) and the Lisa Dean Mosley Foundation (to CE and MH). JV is an Ambrose Monell Cancer Genomic Medicine Fellow (to CE). CE is the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic and is an ACS Clinical Research Professor.

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  1. These authors contributed equally: Shin Chung Kang, Nicholas B. Sarn, Juan Venegas.

Authors and Affiliations

  1. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Shin Chung Kang, Nicholas B. Sarn, Juan Venegas, Zhibing Tan, Masahiro Hitomi & Charis Eng

  2. Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA

    Zhibing Tan, Masahiro Hitomi & Charis Eng

  3. Center for Personalized Genetic Healthcare, Medical Specialties Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Charis Eng

  4. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Charis Eng

  5. Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA

    Charis Eng

  6. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Charis Eng

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SK, MH, ZT performed experiments and data analysis. SK, MH, CE designed experiments, NS, SK, JV wrote the manuscript, JV conducted the transcriptomic analysis, and CE oversaw and manage project design and progress until completion.

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Correspondence to Charis Eng.

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Kang, S.C., Sarn, N.B., Venegas, J. et al. Germline PTEN genotype-dependent phenotypic divergence during the early neural developmental process of forebrain organoids. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02325-3

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