The blind mole rat (BMR), Spalax galili, is an excellent model for studying mammalian adaptation to life underground and medical applications. The BMR spends its entire life underground, protecting itself from predators and climatic fluctuations while challenging it with multiple stressors such as darkness, hypoxia, hypercapnia, energetics and high pathonecity. Here we sequence and analyse the BMR genome and transcriptome, highlighting the possible genomic adaptive responses to the underground stressors. Our results show high rates of RNA/DNA editing, reduced chromosome rearrangements, an over-representation of short interspersed elements (SINEs) probably linked to hypoxia tolerance, degeneration of vision and progression of photoperiodic perception, tolerance to hypercapnia and hypoxia and resistance to cancer. The remarkable traits of the BMR, together with its genomic and transcriptomic information, enhance our understanding of adaptation to extreme environments and will enable the utilization of BMR models for biomedical research in the fight against cancer, stroke and cardiovascular diseases.

Blind subterranean mole rats (Spalax, Spalacidae) evolved adaptive strategies to cope with hypoxia that climaxes during winter floods in their burrows. By using real-time PCR, we compared gene expression oferythropoietin(Epo), a key regulator of circulating erythrocytes, andhypoxia-inducible factor 1α (HIF-1α),Epoexpression inducer, in the kidneys ofSpalaxand white rats,Rattus norvegicus. Our results show significantly higher, quicker, and longer responses to different O₂levels inSpalaxcompared withRattus. (i) In normoxia, bothSpalaxandRattuskidneys produce small amounts ofEpo. Maximal expression ofRattus Epois noticed after a 4-h hypoxia at 6% O₂. Under these conditions,Spalax Epolevels are 3-fold higher than inRattus. After 24 h of 10% O₂,Spalax Eporeaches its maximal expression, remarkably 6-fold higher than the maximum inRattus; (ii) theHIF-1α level in normoxia is 2-fold higher inSpalaxthan inRattus. Spalax HIF-1α achieves maximal expression after 4-h hypoxia at 3% O₂, a 2-fold increase compared with normoxia, whereas no significant change was detected inRattus HIF-1α at any of the conditions studied; (iii) at 6% O₂for 10 h, in whichRattuscannot survive,EpoandHIF-1α levels inSpalax galili, living in heavily flooded soils, are higher than inSpalax judaei, residing in light aerated soil. We suggest that this pattern ofEpoandHIF-1α expression is a substantial contribution to the adaptive strategy of hypoxia tolerance inSpalax, evolved during 40 million years of evolution to cope with underground hypoxic stress.

Background: Subterranean blind mole rats(Spalax)are hypoxia tolerant (down to 3% O₂), long lived (>20 years) rodents showing no clear signs of aging or aging related disorders. In 50 years ofSpalaxresearch, spontaneous tumors have never been recorded among thousands of individuals.Here we addressed the questions of (1) whetherSpalaxis resistant to chemically-induced tumorigenesis, and (2) whether normal fibroblasts isolated fromSpalaxpossess tumor-suppressive activity.Results: Treating animals with 3-Methylcholantrene (3MCA) and 7,12-Dimethylbenz(a) anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA), two potent carcinogens, confirmedSpalaxhigh resistance to chemically induced cancers. While all mice and rats developed the expected tumors following treatment with both carcinogens, amongSpalaxno tumors were observed after DMBA/TPA treatment, while 3MCA induced benign fibroblastic proliferation in 2Spalaxindividuals out of12, and only a single animal from the advanced age group developed malignancy 18 months post-treatment. The remaining animals are still healthy 30 months post-treatment.In vitroexperiments showed an extraordinary ability of normalSpalaxcultured fibroblasts to restrict malignant behavior in a broad spectrum of human-derived and in newly isolatedSpalax3MCA-induced cancer cell lines. Growth of cancer cells was inhibited by either direct interaction withSpalaxfibroblasts or with soluble factors released into culture media and soft agar. This was accompanied by decreased cancer cell viability, reduced colony formation in soft agar, disturbed cell cycle progression, chromatin condensation and mitochondrial fragmentation. Cells from another cancer resistant subterranean mammal, the naked mole rat, were also tested for direct effect on cancer cells and, similar toSpalax, demonstrated anti-cancer activity. No effect on cancer cells was observed using fibroblasts from mouse, rat orAcomys.Spalaxfibroblast conditioned media had no effect on proliferation of noncancerous cells.Conclusions: This report provides pioneering evidence thatSpalaxis not only resistant to spontaneous cancer but also to experimentally induced cancer, and shows the unique ability ofSpalaxnormal fibroblasts to inhibit growth and kill cancer cells, but not normal cells, either through direct fibroblast-cancer cell interaction or via soluble factors. Obviously, along with adaptation to hypoxia,Spalaxhas evolved efficient anti-cancer mechanisms yet to be elucidated. Exploring the molecular mechanisms allowingSpalaxto survive in extreme environments and to escape cancer as well as to kill homologous and heterologous cancer cells may hold the key for understanding the molecular nature of host resistance to cancer and identify new anti-cancer strategies for treating humans.

Lacrimo-auriculo-dento-digital (LADD) syndrome is characterized by abnormalities in lacrimal and salivary glands, in teeth, and in the distal limbs. Genetic studies have implicated heterozygous mutations in fibroblast growth factor 10 (FGF10) and in FGF receptor 2 (FGFR2) in LADD syndrome. However, it is not clear whether LADD syndrome mutations (LADD mutations) are gain- or loss-of-function mutations. In order to reveal the molecular mechanism underlying LADD syndrome, we have compared the biological properties of FGF10 LADD and FGFR2 LADD mutants to the activities of their normal counterparts. These experiments show that the biological activities of three different FGF10 LADD mutants are severely impaired by different mechanisms. Moreover, haploinsufficiency caused by defective FGF10 mutants leads to LADD syndrome. We also demonstrate that the tyrosine kinase activities of FGFR2 LADD mutants expressed in transfected cells are strongly compromised. Since tyrosine kinase activity is stimulated by ligand-induced receptor dimerization, FGFR2 LADD mutants may also exert a dominant inhibitory effect on signaling via wild-type FGFR2 expressed in the same cell. These experiments underscore the importance of signal strength in mediating biological responses and that relatively small changes in receptor signaling may influence the outcome of developmental processes in cells or organs that do not possess redundant signaling pathway.