PMID- 38328230
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240331
DP  - 2024 Jan 25
TI  - Dual effects of ARX poly-alanine mutations in human cortical and interneuron 
      development.
LID - 2024.01.25.577271 [pii]
LID - 10.1101/2024.01.25.577271 [doi]
AB  - Mutations in ARX , an X-linked gene, are implicated in a wide spectrum of 
      neurological disorders including patients who have intellectual disability and 
      epilepsy. Mouse models have shown that Arx is critical for cortical development 
      and interneuron migration, however they do not recapitulate the full phenotype 
      observed in patients. Moreover, the epilepsy in many patients with poly-alanine 
      tract expansion (PAE) mutations in ARX show pharmacoresistance, emphasizing the 
      need to develop new treatments. Here, we used human neural organoid models to 
      study the consequences of PAE mutations, one of the most prevalent mutations in 
      ARX . We found that PAE mutations result in an early increase in radial glia 
      cells and intermediate progenitor cells, and premature differentiation leading to 
      a loss of cortical neurons at later timepoints. Moreover, ARX expression is 
      upregulated in CO derived from patient at 30 DIV which alters the expression of 
      CDKN1C , SFRP1 , DLK1 and FABP7 , among others. We also found a cell autonomously 
      enhanced interneuron migration, which can be rescued by CXCR4 inhibition. 
      Furthermore, ARX (PAE) assembloids had hyper-activity and synchrony evident from 
      the early stages. These data provide novel insights to the pathogenesis of these 
      and likely related human neurological disorders and identifies a critical window 
      for therapeutic interventions.
FAU - Nieto-Estevez, Vanesa
AU  - Nieto-Estevez V
FAU - Varma, Parul
AU  - Varma P
FAU - Mirsadeghi, Sara
AU  - Mirsadeghi S
FAU - Caballero, Jimena
AU  - Caballero J
FAU - Gamero-Alameda, Sergio
AU  - Gamero-Alameda S
FAU - Hosseini, Ali
AU  - Hosseini A
FAU - Goswami, Sonal
AU  - Goswami S
FAU - Silvosa, Marc J
AU  - Silvosa MJ
FAU - Thodeson, Drew M
AU  - Thodeson DM
FAU - Lybrand, Zane R
AU  - Lybrand ZR
FAU - Giugliano, Michele
AU  - Giugliano M
FAU - Navara, Christopher
AU  - Navara C
FAU - Hsieh, Jenny
AU  - Hsieh J
LA  - eng
GR  - R01 NS113516/NS/NINDS NIH HHS/United States
GR  - R01 NS124855/NS/NINDS NIH HHS/United States
GR  - R21 AG066496/AG/NIA NIH HHS/United States
GR  - U01 DA054170/DA/NIDA NIH HHS/United States
PT  - Preprint
DEP - 20240125
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10849640
EDAT- 2024/02/08 06:42
MHDA- 2024/02/08 06:43
PMCR- 2024/02/07
CRDT- 2024/02/08 04:16
PHST- 2024/02/08 06:43 [medline]
PHST- 2024/02/08 06:42 [pubmed]
PHST- 2024/02/08 04:16 [entrez]
PHST- 2024/02/07 00:00 [pmc-release]
AID - 2024.01.25.577271 [pii]
AID - 10.1101/2024.01.25.577271 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2024 Jan 25:2024.01.25.577271. doi: 
      10.1101/2024.01.25.577271.