Dysregulation of mTOR signaling mediates common neurite and migration defects in both idiopathic and 16p11.2 deletion autism neural precursor cells
Abstract
Autism spectrum disorder (ASD) is defined by common behavioral characteristics, raising the possibility of shared pathogenic mechanisms. Yet, vast clinical and etiological heterogeneity suggests personalized phenotypes. Surprisingly, our iPSC studies find that six individuals from two distinct ASD-subtypes, idiopathic and 16p11.2 deletion, have common reductions in neural precursor cell (NPC) neurite outgrowth and migration even though whole genome sequencing demonstrates no genetic overlap between the datasets. To identify signaling differences that may contribute to these developmental defects, an unbiased phospho-(p)-proteome screen was performed. Surprisingly despite the genetic heterogeneity, hundreds of shared p-peptides were identified between autism subtypes including the mTOR pathway. mTOR signaling alterations were confirmed in all NPCs across both ASD-subtypes, and mTOR modulation rescued ASD phenotypes and reproduced autism NPC associated phenotypes in control NPCs. Thus, our studies demonstrate that genetically distinct ASD subtypes have common defects in neurite outgrowth and migration which are driven by the shared pathogenic mechanism of mTOR signaling dysregulation.
Data availability
Genome Wide Sequencing data has been deposited into the NIH NDA. All excel sheets for graphs in the manuscript as well as unedited western blot films (labeled and unlabeled) will be deposited in Dryad: DOI: 10.5061/dryad.6wwpzgn5v
-
Source Data for Dysregulation of mTOR Signaling Mediates Common Neurite and Migration Defects in Both Idiopathic and 16p11.2 Deletion Autism Neural Precursor CellsDryad Digital Repository, doi:10.5061/dryad.6wwpzgn5v.
Article and author information
Author details
Funding
NIH R25 (5R25MH119043-05)
- Smrithi Prem
Rutgers School of Graduate Studies (Thesis Finishing Grant)
- Smrithi Prem
New Jersey Governer's Council For Medical Resear (CAUT13APS010,CAUT14APL031,CAUT15APL041,CAUT19APL014)
- James H Millonig
- Emanuel DiCicco-Bloom
Nancy Lurie Marks Family Foundation
- James H Millonig
- Emanuel DiCicco-Bloom
NJ Health Foundation (PC 63-19)
- James H Millonig
Mindworks Charitable Lead Trust
- Emanuel DiCicco-Bloom
Jewish Community Foundation o Greater MetroWest
- Emanuel DiCicco-Bloom
Autism Science Foundation (Summer Undergraduate Research Grant)
- Cynthia Peng
New Jersey Governor's Council for Medical Research and Treatment of Autism (CAUT19APL028)
- Smrithi Prem
- Jinchuan Xing
- Emanuel DiCicco-Bloom
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2024, Prem et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,731
- views
-
- 224
- downloads
-
- 6
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Developmental Biology
The evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons in Caenorhabditis elegans. Loss of wts-1/LATS, the core kinase of the Hpo pathway, resulted in premature deformation of touch neurons and impaired touch responses in a yap-1/YAP-dependent manner, the downstream transcriptional co-activator of LATS. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule-stabilizing genes alleviated the neuronal deformation of wts-1 mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzyme spas-1 also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in both wts-1-deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.
-
- Developmental Biology
CDK8 and CDK19 paralogs are regulatory kinases associated with the transcriptional Mediator complex. We have generated mice with the systemic inducible Cdk8 knockout on the background of Cdk19 constitutive knockout. Cdk8/19 double knockout (iDKO) males, but not single Cdk8 or Cdk19 KO, had an atrophic reproductive system and were infertile. The iDKO males lacked postmeiotic spermatids and spermatocytes after meiosis I pachytene. Testosterone levels were decreased whereas the amounts of the luteinizing hormone were unchanged. Single-cell RNA sequencing showed marked differences in the expression of steroidogenic genes (such as Cyp17a1, Star, and Fads) in Leydig cells concomitant with alterations in Sertoli cells and spermatocytes, and were likely associated with an impaired synthesis of steroids. Star and Fads were also downregulated in cultured Leydig cells after iDKO. The treatment of primary Leydig cell culture with a CDK8/19 inhibitor did not induce the same changes in gene expression as iDKO, and a prolonged treatment of mice with a CDK8/19 inhibitor did not affect the size of testes. iDKO, in contrast to the single knockouts or treatment with a CDK8/19 kinase inhibitor, led to depletion of cyclin C (CCNC), the binding partner of CDK8/19 that has been implicated in CDK8/19-independent functions. This suggests that the observed phenotype was likely mediated through kinase-independent activities of CDK8/19, such as CCNC stabilization.