skip to content

Overview per year

All :: 1993, ... , 2013, 2014, 2015, 2016
Hatzold, J, Beleggia, F, Herzig, H, Altmuller, J, Nurnberg, P, Bloch, W, Wollnik, B; Hammerschmidt, M
Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit
Elife, 5
ISBN: 2050-084X (Electronic) 2050-084X (Linking)

Keywords: Na/K-ATPase,basal cell carcinogenesis,cancer biology,developmental biology,epithelial polarity,stem cells,zebrafish

Abstract: The molecular pathways underlying tumor suppression are incompletely understood. Here, we identify cooperative non-cell-autonomous functions of a single gene that together provide a novel mechanism of tumor suppression in basal keratinocytes of zebrafish embryos. A loss-of-function mutation in atp1b1a, encoding the beta subunit of a Na,K-ATPase pump, causes edema and epidermal malignancy. Strikingly, basal cell carcinogenesis only occurs when Atp1b1a function is compromised in both the overlying periderm (resulting in compromised epithelial polarity and adhesiveness) and in kidney and heart (resulting in hypotonic stress). Blockade of the ensuing PI3K-AKT-mTORC1-NFkappaB-MMP9 pathway activation in basal cells, as well as systemic isotonicity, prevents malignant transformation. Our results identify hypotonic stress as a (previously unrecognized) contributor to tumor development and establish a novel paradigm of tumor suppression.

Hosseinibarkooie, S, Peters, M, Torres-Benito, L, Rastetter, R H, Hupperich, K, Hoffmann, A, Mendoza-Ferreira, N, Kaczmarek, A, Janzen, E, Milbradt, J, Lamkemeyer, T, Rigo, F, Bennett, C F, Guschlbauer, C, Buschges, A, Hammerschmidt, M, Riessland, M, Kye, M J, Clemen, C S; Wirth, B
The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype
Am J Hum Genet, 99(3):647--665
ISBN: 1537-6605 (Electronic) 0002-9297 (Linking)

Abstract: Homozygous loss of SMN1 causes spinal muscular atrophy (SMA), the most common and devastating childhood genetic motor-neuron disease. The copy gene SMN2 produces only approximately 10% functional SMN protein, insufficient to counteract development of SMA. In contrast, the human genetic modifier plastin 3 (PLS3), an actin-binding and -bundling protein, fully protects against SMA in SMN1-deleted individuals carrying 3-4 SMN2 copies. Here, we demonstrate that the combinatorial effect of suboptimal SMN antisense oligonucleotide treatment and PLS3 overexpression-a situation resembling the human condition in asymptomatic SMN1-deleted individuals-rescues survival (from 14 to \textgreater250 days) and motoric abilities in a severe SMA mouse model. Because PLS3 knockout in yeast impairs endocytosis, we hypothesized that disturbed endocytosis might be a key cellular mechanism underlying impaired neurotransmission and neuromuscular junction maintenance in SMA. Indeed, SMN deficit dramatically reduced endocytosis, which was restored to normal levels by PLS3 overexpression. Upon low-frequency electro-stimulation, endocytotic FM1-43 (SynaptoGreen) uptake in the presynaptic terminal of neuromuscular junctions was restored to control levels in SMA-PLS3 mice. Moreover, proteomics and biochemical analysis revealed CORO1C, another F-actin binding protein, whose direct binding to PLS3 is dependent on calcium. Similar to PLS3 overexpression, CORO1C overexpression restored fluid-phase endocytosis in SMN-knockdown cells by elevating F-actin amounts and rescued the axonal truncation and branching phenotype in Smn-depleted zebrafish. Our findings emphasize the power of genetic modifiers to unravel the cellular pathomechanisms underlying SMA and the power of combinatorial therapy based on splice correction of SMN2 and endocytosis improvement to efficiently treat SMA.

Jeradi, S; Hammerschmidt, M
Retinoic acid-induced premature osteoblast-to-preosteocyte transitioning has multiple effects on calvarial development
Development, 143(7):1205--1216
ISBN: 1477-9129 (Electronic) 0950-1991 (Linking)

Keywords: Animals,Animals, Genetically Modified,Benzothiazoles/pharmacology,Bone development,Cell Differentiation/physiology,Cytochrome P-450 Enzyme System/ genetics,Diversity,Gene Expression Regulation, Developmental,Metronidazole/pharmacology,Osteoblasts/ cytology,Osteoclasts/cytology,Osteocytes/ cytology,Osteogenesis/genetics/ physiology,Retinoic acid,Skull/abnormalities/ embryology,Tretinoin/ pharmacology,Triazoles/pharmacology,Zebrafish,Zebrafish Proteins/antagonists & inhibitors/ genetics,Zebrafish/ embryology

Abstract: We have previously shown that, in human and zebrafish, hypomorphic mutations of the gene encoding the retinoic acid (RA)-metabolizing enzyme Cyp26b1 result in coronal craniosynostosis, caused by an RA-induced premature transitioning of suture osteoblasts to preosteocytes, inducing ectopic mineralization of the suture's osteoid matrix. In addition, we showed that human CYP26B1 null patients have more severe and seemingly opposite skull defects, characterized by smaller and fragmented calvaria, but the cellular basis of these defects remained largely unclear. Here, by treating juvenile zebrafish with exogenous RA or a chemical Cyp26 inhibitor in the presence or absence of osteogenic cells or bone-resorbing osteoclasts, we demonstrate that both reduced calvarial size and calvarial fragmentation are also caused by RA-induced premature osteoblast-to-preosteocyte transitioning. During calvarial growth, the resulting osteoblast deprival leads to decreased osteoid production and thereby smaller and thinner calvaria, whereas calvarial fragmentation is caused by increased osteoclast stimulation through the gained preosteocytes. Together, our data demonstrate that RA-induced osteoblast-to-preosteocyte transitioning has multiple effects on developing bone in Cyp26b1 mutants, ranging from gain to loss of bone, depending on the allelic strength, the developmental stage and the cellular context.

Richardson, R; Hammerschmidt, M
The role of Rho kinase (Rock) in re-epithelialization of adult zebrafish skin wounds
Small GTPases, :1--7
ISBN: 2154-1256 (Electronic) 2154-1248 (Linking)

Keywords: Re-epithelialization,Rho kinase,cellular rearrangements,collective cell migration,radial intercalation,rock,skin,wound healing,zebrafish

Abstract: Complete re-epithelialization of full-thickness skin wounds in adult mammals takes days to complete and relies on numerous signaling cues and multiple overlapping cellular processes that take place both within the epidermis itself and in other participating tissues. We have previously shown that re-epithelialization of full-thickness skin wounds of adult zebrafish, however, is extremely rapid and largely independent of the other processes of wound healing allowing for the dissection of specific processes that occur in, or have a direct effect on, re-epithelializing keratinocytes. Recently, we have shown that, in addition to lamellipodial crawling at the leading edge, re-epithelialization of zebrafish partial- and full-thickness wounds requires long-range epithelial rearrangements including radial intercalations, flattening and directed elongation and that each of these processes involves Rho kinase (Rock) signaling. Our studies demonstrate how these coordinated signaling events allow for the rapid collective cell migration observed in adult zebrafish wound healing. Here we discuss the particular contribution of Rock to each of these processes.

Richardson, R, Metzger, M, Knyphausen, P, Ramezani, T, Slanchev, K, Kraus, C, Schmelzer, E; Hammerschmidt, M
Re-epithelialization of cutaneous wounds in adult zebrafish combines mechanisms of wound closure in embryonic and adult mammals
Development, 143(12):2077--2088
ISBN: 1477-9129 (Electronic) 0950-1991 (Linking)

Keywords: Cell proliferation,Fgf,Re-epithelialization,Skin,TGF-beta,Wound healing

Abstract: Re-epithelialization of cutaneous wounds in adult mammals takes days to complete and relies on numerous signalling cues and multiple overlapping cellular processes that take place both within the epidermis and in other participating tissues. Re-epithelialization of partial- or full-thickness skin wounds of adult zebrafish, however, is extremely rapid and largely independent of the other processes of wound healing. Live imaging after treatment with transgene-encoded or chemical inhibitors reveals that re-epithelializing keratinocytes repopulate wounds by TGF-beta- and integrin-dependent lamellipodial crawling at the leading edges of the epidermal tongue. In addition, re-epithelialization requires long-range epithelial rearrangements, involving radial intercalations, flattening and directed elongation of cells - processes that are dependent on Rho kinase, JNK and, to some extent, planar cell polarity within the epidermis. These rearrangements lead to a massive recruitment of keratinocytes from the adjacent epidermis and make re-epithelialization independent of keratinocyte proliferation and the mitogenic effect of FGF signalling, which are only required after wound closure, allowing the epidermis outside the wound to re-establish its normal thickness. Together, these results demonstrate that the adult zebrafish is a valuable in vivo model for studying and visualizing the processes involved in cutaneous wound closure, facilitating the dissection of direct from indirect and motogenic from mitogenic effects of genes and molecules affecting wound re-epithelialization.

Export as: