Biology subjects

Kaartinen, V.

Publications and source records attributed to Kaartinen, V..

6 recordsLinked to original sources

bioRxiv2026

TGF-b/TIF1g signaling restrains CD8+ T cell expansion while preserving cytotoxic competence

Transforming growth factor b exerts complex and often opposing effects on CD8+ T cell biology, yet the molecular mechanisms that distinguish these functions remain poorly understood. Here, we identify TIF1g (TRIM33) as a critical signal threshold regulator that couples TGF b signaling to CD8+ T cell activation and cytotoxic function. In the presence of TGF b, TIF1g deficient CD8+ T cells bypass canonical suppressive signals and acquire a transcriptional program characterized by enhanced activation and proliferation. Despite this hyperactivated state, TIF1g deficient cells fail to acquire full effector function, exhibiting markedly reduced Granzyme B and Perforin expression under TGF b signaling. We confirmed this functional uncoupling in vivo using a secondary Listeria monocytogenes challenge model, in which TIF1g deficient CD8+ T cells underwent robust expansion yet failed to efficiently control bacterial infection because of impaired cytotoxic activity. In a lymphopenic homeostatic proliferation model, TIF1g deficiency disrupted cellular quiescence, leading to excessive proliferation and spontaneous effector differentiation. Consistent with these findings, loss of TIF1g accelerated B16 melanoma growth and was associated with reduced Perforin expression in tumor-infiltrating CD8+ T cells. Together, these findings identify TIF1g as a key regulator of TGF b mediated CD8+ T cell responses, uncoupling activation from cytotoxic differentiation and revealing a mechanism by which TGF b independently regulates proliferative and effector programs.

immunology↗

bioRxiv2025

A lipid metabolism defect is an underlying contributor to Diamond Blackfan anemia syndrome

Analysis of neither Diamond Blackfan anemia syndrome (DBAS) cohorts nor animal models has revealed a potential mechanism for the variable anemia phenotype, a key feature of this disease. Here, we utilized an established Rpl5Skax23-Jus/+ murine DBAS model in order to study this dynamic erythropoiesis deficiency. These haploinsufficient mice exhibit variably penetrant craniofacial and cardiac defects mimicking the phenotypes of DBAS patients bearing RPL5 mutations. We additionally discovered that this specific heterozygous splicing mutation is pathogenic and leads to partial intron retention. By examining the transcriptome of fetal liver erythroid progenitors at E12.5, we demonstrate that the downregulation of erythroid differentiation pathways is consistent with the DBAS phenotype. We also identified dysregulated transcription of lipid metabolism genes with significant reduction in the abundance of Scd1 in a subset of E12.5 mutant embryos at risk for erythroid failure. SCD1, a key enzyme that converts saturated to monounsaturated fatty acids, has not been previously linked to erythropoiesis or DBAS. When anemia was induced in adult mice, pretreatment with an SCD1 inhibitor resulted in improved erythropoiesis. This analysis suggests a key role of lipid metabolism in the variable anemia penetrance in DBAS and highlights a previously unappreciated pathway that may serve as a potential target for drug development. Key PointsO_LIThe variable anemia in Rpl5Skax23-Jus/+mice is triggered by intrinsic/extrinsic stress C_LIO_LIRpl5 haploinsufficient murine and human erythroid progenitors exhibit a lipid metabolism signature with downregulation of Scd1/SCD. C_LI

developmental biology↗

bioRxiv2024

TIF1γ regulates stability of T regulatory cells during inflammation

T regulatory cells are a suppressor population critical to control inflammation and maintain tissue homeostasis. The TGF-{beta} pathway is a fundamental signal for T regulatory cell differentiation, yet the molecular determinants of how TGF-{beta} signals regulate all these processes are not completely understood. TIF1{gamma} was demonstrated to promote a noncanonical TGF-{beta}/Smad pathway in HSC, however the role of TIF1{gamma} in Treg function has been largely ignored. Here we showed that TIF1{gamma} deficient Tregs lose stability and acquire an effector phenotype in the presence of an inflammatory stimuli or upon activation. TIF1{gamma} deficient T regs gain a Th1-like Treg phenotype or become pro-inflammatory exTregs, by losing Foxp3 expression and acquiring IFN{gamma} expression in an autoimmune model. Loss of TIF1{gamma} in Tregs was cell-intrinsic and was also accompanied by increased proliferation and enhanced glycolytic capacity upon activation. Additionally, we demonstrated that in the absence of TIF1{gamma}, there was an increased methylation status in the CNS2 enhancer region of the Foxp3 locus, further suggesting increased susceptibility for loss of Foxp3 expression. Mechanistically, TGF-{beta} was in part responsible to inhibit the Th1-like bias a Treg has in the absence of TIF1{gamma}, however, the proliferative phenotype observed in these cells was mostly independent of TGF-{beta} signaling. Finally, we identified the beta-catenin pathway as the molecular mechanism driving both TIF1{gamma}-dependent Treg stability and proliferation upon inflammation. Altogether, our data demonstrated that TIF1{gamma} is required for the maintenance of a suppressor phenotype and stability of Treg lymphocytes during inflammatory conditions in vivo and represents a new modulatory pathway to manipulate Treg cells for therapeutic purposes.

immunology↗

bioRxiv2024

TGF-β Signaling in Cranial Neural Crest Affects Late-Stage Mandibular Bone Resorption and Length

Malocclusions are common craniofacial malformations which cause quality of life and health problems if left untreated. Unfortunately, the current treatment for severe skeletal malocclusion is invasive surgery. Developing improved therapeutic options requires a deeper understanding of the cellular mechanisms responsible for determining jaw bone length. We have recently shown that neural crest mesenchyme (NCM) can alter jaw length by controlling recruitment and function of mesoderm-derived osteoclasts. Transforming growth factor beta (TGF-{beta}) signaling is critical to craniofacial development by directing bone resorption and formation, and heterozygous mutations in TGF-{beta} type I receptor (TGFBR1) are associated with micrognathia in humans. To identify what role TGF-{beta} signaling in NCM plays in controlling osteoclasts during mandibular development, mandibles of mouse embryos deficient in the gene encoding Tgfbr1 specifically in NCM were analyzed. Our lab and others have demonstrated that Tgfbr1fl/fl;Wnt1-Cre mice display significantly shorter mandibles with no condylar, coronoid, or angular processes. We hypothesize that TGF-{beta} signaling in NCM can also direct later bone remodeling and further regulate late embryonic jaw bone length. Interestingly, analysis of mandibular bone through micro-computed tomography and Massons trichrome revealed no significant difference in bone quality between the Tgfbr1fl/fl;Wnt1-Cre mice and controls, as measured by bone perimeter/bone area, trabecular rod-like diameter, number and separation, and gene expression of Collagen type 1 alpha 1 (Col11) and Matrix metalloproteinase 13 (Mmp13). Though there was not a difference in localization of bone resorption within the mandible indicated by TRAP staining, Tgfbr1fl/fl;Wnt1-Cre mice had approximately three-fold less osteoclast number and perimeter than controls. Gene expression of receptor activator of nuclear factor kappa-{beta} (Rank) and Mmp9, markers of osteoclasts and their activity, also showed a three-fold decrease in Tgfbr1fl/fl;Wnt1-Cre mandibles. Evaluation of osteoblast-to-osteoclast signaling revealed no significant difference between Tgfbr1fl/fl;Wnt1-Cre mandibles and controls, leaving the specific mechanism unresolved. Finally, pharmacological inhibition of Tgfbr1 signaling during the initiation of bone mineralization and resorption significantly shortened jaw length in embryos. We conclude that TGF-{beta} signaling in NCM decreases mesoderm-derived osteoclast number, that TGF-{beta} signaling in NCM impacts jaw length late in development, and that this osteoblast-to-osteoclast communication may be occurring through an undescribed mechanism.

developmental biology↗

bioRxiv2021

A unique form of collective epithelial migration is crucial for tissue fusion in the secondary palate and can overcome loss of epithelial apoptosis

Tissue fusion is an oft-employed process in morphogenesis which often requires the removal of the epithelia intervening multiple distinct primordia to form one continuous structure. In the mammalian secondary palate, a midline epithelial seam (MES) forms between two palatal shelves and must be removed to allow mesenchymal confluence. Abundant apoptosis and cell extrusion in this epithelial seam support their importance in its removal. However, by genetically disrupting the intrinsic apoptotic regulators BAX and BAK within the MES, we find a complete loss of cell death and cell extrusion, but successful removal of the MES, indicating that developmental compensation enables fusion. Novel static and live imaging approaches reveal that the MES is removed through a unique form of collective epithelial cell migration in which epithelial trails and islands stream through the mesenchyme to reach the oral and nasal epithelial surfaces. These epithelial trails and islands begin to express periderm markers while retaining expression of the basal epithelial marker {Delta}Np63, suggesting their migration to the oral and nasal surface is concomitant with their differentiation to an epithelial intermediate. Live imaging reveals anisotropic actomyosin contractility within epithelial trails that drives their peristaltic movement, and genetic loss of non-muscle myosin IIA-mediated actomyosin contractility results in dispersion of epithelial collectives and dramatic failure of normal MES migration. These findings demonstrate redundancy between cellular mechanisms of morphogenesis and reveal a crucial role for a unique form of collective epithelial migration during tissue fusion.

developmental biology↗

bioRxiv2021

A new murine Rpl5 (uL18) mutation provides a unique model of variably penetrant Diamond Blackfan Anemia

Ribosome dysfunction is implicated in multiple abnormal developmental and disease states in humans. Heterozygous germline mutations in genes encoding ribosomal proteins (RPs) are found in the majority of individuals with Diamond Blackfan anemia (DBA) while somatic mutations have been implicated in a variety of cancers and other disorders. Ribosomal protein-deficient animal models show variable phenotypes and penetrance, similar to human DBA patients. The spontaneous anemia remission observed in some DBA patients occurs via unknown mechanism(s) and has not been previously described in animal models. Here we characterized a novel ENU mouse mutant (Skax23m1Jus) with growth and skeletal defects, cardiac malformations and increased mortality. Following genetic mapping and whole exome sequencing, we identified an intronic Rpl5 mutation, which segregated with all affected mice. This mutation was associated with decreased ribosome generation, consistent with Rpl5 haploinsufficiency. Rpl5Skax23-Jus mutant animals had a profound delay in erythroid maturation and increased mortality at embryonic day E12.5, which improved by E14.5. Surviving mutant animals had a macrocytic anemia at birth as well as evidence of ventricular septal defect (VSD). Surviving adult and aged mice exhibited no hematopoietic defect or VSD. We propose that this novel Rpl5Skax23-Jus mutant mouse will be useful to study the factors influencing the variable penetrance and anemia remission that are observed in DBA.

developmental biology↗