Evidence of shared transcriptomic dysregulation of HNRNPU-related disorder between human organoids and embryonic mice

Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis

“…Accordingly, we hypothesize that the observed downregulation of the synaptic and neuronal maturation markers is due to abnormal enrichment of progenitor at D28 stage and a consequence of the delayed maturation process. This observation is in contrast with what was observed in a recently published study on human cortical organoids, where HNRNPU mutations are shown to associate with downregulation of ontologies referring to nucleic acid binding and upregulation of neurogenic pathways (Ressler et al, 2023). The dysregulated genes are partially resembling transcriptomic alterations in embryonic mice carrying a heterozygous mutation in HNRNPU but are discordant with the perinatal mice.…”

“…In parallel, we analyzed cerebellar marker expression in our previously published single-cell RNA-seq (scRNAseq) data from a similarly derived cell line at D28(Becker et al, 2020) and showed that the cerebellar markers are indeed expressed across the cell types ( Figure S1J ). Furthermore, to evaluate the specificity of our model, we analyzed the expression of the markers in a previously published dataset from human cortical organoids(Ressler et al, 2023) and observed extremely low or null expression of the markers in all the cell types and samples ( Figure S1K ).…”

“…HNRNPU expression follows a similar decreasing trend during differentiation from iPSCs to neurons from a previously published dataset(Burke et al, 2020) and during development of all the cerebral areas, although in the cerebellum the postnatal expression is the highest compared to the other brain regions ( Figure 1G, Figure S1L). Since HNRNPU expression was higher in proliferating progenitor cells ( Figure 1D and (Ressler et al, 2023; Sapir et al, 2022)), we further inspected its expression in our above mentioned scRNA-seq data ( Figure S2A ). As expected, HNRNPU expression was highest in the neural progenitor population ( Figure S2B-C ).…”

“…NPC=Neural progenitor cell. K) Expression of cerebellar markers among cell types and across samples in organoid scRNA-seq data(Ressler et al, 2023). D11= HNRNPU deficient organoids with a heterozygous frameshift mutation, M20= HNRNPU deficient organoids with a heterozygous premature termination codon, PGP1=Control organoids.…”

HNRNPU's multi‐tasking is essential for proper cortical development

“…[97] The lethality of homozygous embryos was also noted when a conditional Hnrnpu allele was excised in the female germ line. [87] Mice heterozygous for Hnrnpu loss of function mutation [98] and conditional deletion mutations of Hnrnpu in either the mouse heart [87] or brain [49] are viable and yielded some insight into the developmental role of HNRNPU/SAF-A. Ye et al attempted to dissect HNRNPU's RNA-and DNA-binding functions by engineering floxed sites flanking exons 4-14 into the Hnrnpu genomic mouse locus.…”