Riedhammer, K. M. | bioRxiv Science

bioRxiv2025

A kidney specific mouse model to study the effects of in vivo induction of Yamanaka factors

IntroductionMaladaptive repair after acute kidney injury (AKI) leads to fibrosis and chronic kidney disease (CKD). Improving the resilience and stimulating tissue repair after injury is crucial to prevent AKI-to-CKD transition. Using a combination of transcription factors (Yamanaka factors Oct4, Klf4 and Sox2, "OKS") to partially reprogram tissues and enhance regeneration in vivo, could be a promising approach as shown by amelioration after various organ injury, yet not investigated for AKI to date. MethodsWe used a ubiquitously and kidney-specific transgenic mouse model to investigate OKS expression in kidney. In a kidney-specific model using Pax8-Cre, we then induced AKI via aristolochic acid (AA), simultaneously expressing OKS to determine potential protective effects after kidney injury. ResultsWe show that a ubiquitously expressing OKS-mouse model was not suitable due to toxic effects and limited kidney expression. In the Pax8-Cre mouse model, we observed expression almost exclusively to proximal tubules. While induction for more than 3 days caused dysplastic tumor formation, an induction regimen limited to 3 days was not able to improve phenotypic outcome after AA-injury. ConclusionPartial reprogramming of the kidney using OKS is feasible; however, it requires a delicate balance to the risk of oncogenic transformation. Determine a dose that effectively promotes repair without crossing the threshold into harmful effects remains a major challenge, posing significant safety concerns for translating the approach to humans in the near future.

developmental biology↗

bioRxiv2019

Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as Loss-of-Function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila Melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

genetics↗