The inner ear houses two sensory modalities: the hearing organ, located in the cochlea, and the balance organs, located throughout the vestibular regions of the ear. Both hearing and vestibular sensory regions are composed of similar cell types, including hair cells and associated supporting cells. Recently, we showed that Notch1 is required for maintaining supporting cell survival postnatally during cochlear maturation. However, it is not known whether Notch1 plays a similar role in the balance organs of the inner ear. To characterize the role of Notch during vestibular maturation, we conditionally deleted Notch1 from Sox2-expressing cells of the vestibular organs in the mouse at P0/P1. Histological analyses showed a dramatic loss of supporting cells accompanied by an increase in type II hair cells without cell death, indicating the supporting cells are converting to hair cells in the maturing vestibular regions. Analysis of 6-week old animals indicate that the converted hair cells survive, despite the reduction of supporting cells. Interestingly, measurements of vestibular sensory evoked potentials (VsEPs), known to be generated in the striolar regions of the vestibular afferents in the maculae, failed to show a response, indicating that NOTCH1 expression is critical for striolar function postnatally. Consistent with this, we find that the specialized type I hair cells in the striola fail to develop the complex calyces typical of these cells. These defects are likely due to the reduction in supporting cells, which have previously been shown to express factors critical for the striolar region. Similar to other mutants that lack proper striolar development, Notch1 mutants do not exhibit typical vestibular behaviors such as circling and head shaking, but do show difficulties in some vestibular tests, including the balance beam and forced swim test. These results indicate that, unlike the hearing organ in which the supporting cells undergo cell death, supporting cells in the balance regions retain the ability to convert to hair cells during maturation, which survive into adulthood despite the reduction in supporting cells.

Notch is a conserved cell-signaling pathway involved in spermatogenesis regulation. This study firstly evaluated the presence, localization patterns, acquisition origin and relation to acrosome reaction of Notch proteins in bull sperm. Western Blot analysis detected all Notch proteins in ejaculated bull sperm, and immunostaining described their specific sperm localization. Recovery of sperm from different segments showed that Notch proteins have testicular origin (NOTCH1, NOTCH2, DLL4), are sequentially acquired during sperm maturation along epididymal transit (NOTCH3, DLL3, JAGGED1-2), or post-ejaculation (DLL1, NOTCH4). Testis NOTCH2 is ubiquitously expressed in all germ-cell lines, whereas DLL4 is expressed in round and elongated spermatids during the Golgi, Cap, Acrosome and Maturation phases. In vitro spontaneous and induced sperm acrosome reaction induce consistent sperm regional relocation of NOTCH2, DLL4 and JAGGED1, and these relocation patterns are significantly associated to sperm acrosome status. NOTCH2 and JAGGED1 are relocated from the head apical to the post-equatorial regions, whereas DLL4 is lost along with the acrosome, evidencing that sperm spatial redistribution of NOTCH2 and JAGGED1 is linked to acrosome reaction onset, whereas DLL4 loss is linked to AR completion. Overall, results prompt for a relevant Notch role in bull sperm acrosome testicular development, epididymal maturation and acrosome reaction.

Exposure to ionizing radiation is associated with an increased risk of hematologic malignancies in myeloid and lymphoid lineages in humans and experimental mice. Given that substantial evidence links radiation exposure with the risk of hematologic malignancies, it is imperative to deeply understand the mechanisms underlying cellular and molecular changes during the latency period between radiation exposure and the emergence of fully transformed malignant cells. One experimental model widely used in the field of radiation and cancer biology to study hematologic malignancies induced by radiation exposure is mouse models of radiation-induced thymic lymphoma. Murine radiation-induced thymic lymphoma is primarily driven by aberrant activation of Notch signaling, which occurs frequently in human precursor T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (T-ALL). Here, we summarize the literature elucidating cell-autonomous and non-cell-autonomous mechanisms underlying cancer initiation, progression, and malignant transformation in the thymus following total-body irradiation (TBI) in mice.

Cardiomyocytes are the largest cell type that make up the heart and confer beating activity to the heart. The proper differentiation of cardiomyocytes relies on the efficient transmission and perception of differentiation cues from several signaling pathways that influence cardiomyocyte-specific gene expression programs. Signaling pathways also mediate intercellular communications to promote proper cardiomyocyte differentiation. We have reviewed the major signaling pathways involved in cardiomyocyte differentiation, including the BMP, Notch, sonic hedgehog, Hippo, and Wnt signaling pathways. Additionally, we highlight the differences between different cardiomyocyte cell lines and the use of these signaling pathways in the differentiation of cardiomyocytes from stem cells. Finally, we conclude by discussing open questions and current gaps in knowledge about the in vitro differentiation of cardiomyocytes and propose new avenues of research to fill those gaps.

HER2-positive breast cancer, characterised by overexpressed HER2 levels, is associated with aggressive tumour behaviour and poor prognosis. Trastuzumab is a standard treatment; however, approximately 50% of patients develop resistance within one year. This study investigates the role of ITGβ3 in promoting stemness and resistance in HER2-positive breast cancer cell lines (HCC1599 and SKBR3). The findings demonstrate that chronic exposure to trastuzumab upregulates stem cell markers (SOX2, OCT4, KLF4, NANOG, SALL4, ALDH, BMI1, Nestin, Musashi 1, TIM3, CXCR4). Given the documented role of RGD-binding integrins in drug resistance and stemness, we specifically investigated their impact on resistant cells. Overexpression of ITGβ3 enhances the expression of these stem cell markers, while silencing ITGβ3 reduces their expression, suggesting a major role for ITGβ3 in maintaining stemness and resistance. Further analysis reveals that ITGβ3 activates the Notch signalling pathway, known for regulating stem cell maintenance. The combination of trastuzumab and cilengitide, an integrin inhibitor, significantly decreases the expression of stem cell markers in resistant cells, indicating a potential therapeutic strategy to overcome resistance. These results identify the importance of ITGβ3 in mediating stemness and trastuzumab resistance through Notch signalling in HER2-positive breast cancer, offering new approaches for enhancing treatment efficacy.

Notch proteins undergo ligand-induced proteolysis to release a nuclear effector that influences a wide range of cellular processes by regulating transcription. Despite years of study, however, how Notch induces the transcription of its target genes remains unclear. Here, we comprehensively examined the response to human Notch1 across a time course of activation using genomic assays of nascent RNA and chromatin accessibility. These data revealed that Notch induces target gene transcription primarily by releasing paused RNA polymerase II (RNAPII), in contrast to prevailing models suggesting that Notch acts by promoting chromatin accessibility. Indeed, we found that open chromatin is established at Notch-responsive regulatory elements prior to Notch signaling, through SWI/SNF-mediated remodeling. Notch activation, however, elicited no further chromatin opening at these loci. Together, these studies reveal that the nuclear response to Notch signaling is dictated by the pre-existing chromatin state and RNAPII distribution at time of signal activation.

A cell is a dynamic system in which various processes occur simultaneously. In particular, intra- and intercellular signaling pathway crosstalk has a significant impact on a cell\'s life cycle, differentiation, proliferation, growth, regeneration, and, consequently, on the normal functioning of an entire organ. Hippo signaling and YAP/TAZ nucleocytoplasmic shuttling play a pivotal role in normal development, homeostasis, and tissue regeneration, particularly in lung cells. Intersignaling communication has a significant impact on the core components of the Hippo pathway and on YAP/TAZ localization. This review describes the crosstalk between Hippo signaling and key lung signaling pathways (WNT, SHH, TGFβ, Notch, Rho, and mTOR) using lung cells as an example and highlights the remaining unanswered questions.

UNASSIGNED: Adult neurogenesis, the process of generating new neurons, continues throughout life. Unfortunately, this process is insufficient in pathological conditions and needs to be promoted. Crocin, the active component of saffron, affects neurogenesis in vivo and in vitro. We aimed to investigate the enhancing effects of crocin on the neurogenesis of adipose-derived mesenchymal stem cells in the presence of retinoic acid, as well as the molecular pathways involved.
UNASSIGNED: Differentiation capacities and stemness potential of harvested ADSCs were evaluated by differentiating into osteocytes and adipocytes, and expression of mesenchymal CD markers by flow cytometry. The optimum dose of crocin was assessed with an MTT assay. Crocin, retinoic acid, CREB/BDNF, and Notch inhibitors and their combination were added to the culture medium. Jag1, Hes1, Notch, and BDNF gene expression were analyzed by RT-PCR on days 7, 14, and 21, while CREB, DCX, SOX2, and NeuN expression were analyzed by immunofluorescence.
UNASSIGNED: Expression of mesenchymal CD markers as well as adipogenic and osteogenic differentiation confirmed the origin and properties of ADSCs. The optimal dose of crocin was 1 mM. Crocin significantly (P<0.05) increased, while inhibitors (DATP&Naphthol) significantly (P<0.05) decreased Jag1, Hes1, Notch, and BDNF expression. Immunofluorescent assessments showed that expression of DCX, BDNF, NeuN, and Sox2 proteins increased significantly (P<0.05) after crocin administration and decreased significantly (P<0.05) after inhibitor administration.
UNASSIGNED: Crocin can be used as an enhancer for neural differentiation of MSCs in vitro in the presence of retinoic acid. The mechanism is proposed through Notch and CREB/BDNF signaling pathways.

[This corrects the article DOI: 10.3389/fncel.2024.1347980.].

Colorectal cancer (CRC) is the third most frequently found cancer in the world, and it is frequently discovered when it is already far along in its development. About 20% of cases of CRC are metastatic and incurable. There is more and more evidence that colorectal cancer stem cells (CCSCs), which are in charge of tumor growth, recurrence, and resistance to treatment, are what make CRC so different. Because we know more about stem cell biology, we quickly learned about the molecular processes and possible cross-talk between signaling pathways that affect the balance of cells in the gut and cancer. Wnt, Notch, TGF-β, and Hedgehog are examples of signaling pathway members whose genes may change to produce CCSCs. These genes control self-renewal and pluripotency in SCs and then decide the function and phenotype of CCSCs. However, in terms of their ability to create tumors and susceptibility to chemotherapeutic drugs, CSCs differ from normal stem cells and the bulk of tumor cells. This may be the reason for the higher rate of cancer recurrence in patients who underwent both surgery and chemotherapy treatment. Scientists have found that a group of uncontrolled miRNAs related to CCSCs affect stemness properties. These miRNAs control CCSC functions like changing the expression of cell cycle genes, metastasis, and drug resistance mechanisms. CCSC-related miRNAs mostly control signal pathways that are known to be important for CCSC biology. The biomarkers (CD markers and miRNA) for CCSCs and their diagnostic roles are the main topics of this review study.