Biology subjects

Parichha, A.

Publications and source records attributed to Parichha, A..

4 recordsLinked to original sources

bioRxiv2026

Cajal-Retzius fate specification is disrupted by constitutive activation of β-Catenin in hem progenitors

Cajal-Retzius cells (CR cells) are the earliest born neurons in the cerebral cortex, and have been implicated in regulating neuronal migration and development of circuitry. A major source of CR cells is the cortical hem, a signaling center at the dorsal telencephalic midline. The hem functions as the hippocampal organizer via canonical WNT signaling and hem progenitors are therefore exposed to high levels of WNT ligands. We tested whether constitutive stabilization of {beta}-Catenin (gain of function, GOF) in the mouse cortical hem progenitors supports CR cell production. We find that although neurons are produced from the hem, they do not acquire molecular features of CR cell identity. The trajectory of differentiation examined using single-cell transcriptomics reveals that immature CR cells normally display a Tbr2+ stage, which is absent upon {beta}-Catenin GOF. These data indicate that CR progenitors in the hem are sensitive to levels of stabilized {beta}-Catenin and that a Tbr2+ stage may be important for the acquisition of CR cell identity.

developmental biology↗

bioRxiv2025

TRF2 Non-Telomeric Function is Indispensable for Neural stemness

Depletion of TRF2 from chromosome ends results in telomeric fusions and genome instability in mammals. Here we show that although TRF2 is indispensable for the proliferation and survival of mouse neural stem cells (mNSCs), surprisingly, this is due to non-telomeric transcriptional function of TRF2, and not telomere protection. Complementing recent work showing TRF2 is dispensable for telomere protection in pluripotent stem cells. Deletion of TRF2 in adult mNSCs (TRF2fl/fl, Nestin-Cre) resulted in markedly reduced proliferation and impaired differentiation into neurons. However, telomere dysregulation-induced DNA damage was not observed, as indicated by the unaltered DNA damage response. Similarly, in SH-SY5Y cells, TRF2 depletion induced differentiation without causing telomere dysfunction. Mechanistically, non-telomeric TRF2 directly binds to the promoters of key genes that regulate differentiation. TRF2-dependent recruitment of the polycomb repressor complex (PRC2) and subsequent H3K27 trimethylation repress differentiation-associated genes, thereby maintaining NSC identity. Interestingly, G-quadruplex (G4) motifs are necessary for TRF2 binding. Disrupting the TRF2-G4 interaction-- either through G4-binding ligands or the G4-specific helicase DHX36--induces differentiation genes, thereby promoting neurogenesis. These findings reveal a pivotal non-telomeric role of TRF2 in NSC survival, providing key mechanistic insights into neurogenesis with implications for aging-related neurodegeneration.

molecular biology↗

bioRxiv2022

Dentate gyrus morphogenesis is regulated by β-CATENIN function in hem-derived fimbrial glia.

The dentate gyrus, a gateway for input to the hippocampal formation, arises from progenitors in the medial telencephalic neuroepithelium adjacent to the cortical hem. Dentate progenitors navigate a complex migratory path guided by two cell populations that arise from the hem, the fimbrial glia, and Cajal-Retzius (CR) cells. Since the hem expresses multiple Wnt genes, we examined whether {beta}-CATENIN, which mediates canonical Wnt signaling and also participates in cell adhesion, is necessary for the development of hem-derived lineages. We report that the fimbrial glial scaffold is disorganized and CR cells are mispositioned upon hem-specific disruption of {beta}-CATENIN. Consequently, the dentate migratory stream is severely affected, and the dentate gyrus fails to form. Using selective Cre drivers, we further determined that {beta}-CATENIN function is required in the fimbrial glial scaffold, but not in the CR cells, for guiding the dentate migration. Our findings highlight a primary requirement for {beta}-CATENIN for the organization of the fimbrial scaffold and a secondary role for this factor in dentate gyrus morphogenesis.

neuroscience↗

bioRxiv2020

Canonical Wnt signaling exerts bidirectional control on choroid plexus epithelial development

The choroid plexus (ChP) secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the ChP epithelium (ChPe) arises from the Wnt-expressing cortical hem. Embryonic mouse and human ChPe both express nuclear {beta}-CATENIN, a canonical Wnt signaling pathway effector, indicating that this pathway is active during ChPe development. Point mutations in human {beta}-CATENIN result in the constitutive activation of canonical Wnt signaling. In a mouse model that recapitulates this perturbation, we report a loss of ChPe identity and an apparent transformation of the ChPe to a neuronal identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell (hESC)-derived organoids. The ChPe is also disrupted when {beta}-Catenin is conditionally inactivated in the mouse. Together, our results indicate that canonical Wnt signaling is required in a precise and regulated manner for normal ChPe development in the mammalian brain.

developmental biology↗