No abstract

The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary resistance to cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the cancer resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed ''early contact inhibition.'' Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27 Kip1 . In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16 Ink4a . Furthermore, we show that the roles of p16 Ink4a and p27 Kip1 in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16 Ink4a , and regular contact inhibition is controlled by p27 Kip1 . We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor resistance of the naked mole-rat.longevity ͉ p16Ink4a ͉ p53 ͉ pRb ͉ tumor suppressor

SummaryIn multicellular organisms, telomerase is required to maintain telomere length in the germline but is dispensable in the soma. Mice, for example, express telomerase in somatic and germline tissues, while humans express telomerase almost exclusively in the germline. As a result, when telomeres of human somatic cells reach a critical length the cells enter irreversible growth arrest called replicative senescence. Replicative senescence is believed to be an anticancer mechanism that limits cell proliferation. The difference between mice and humans led to the hypothesis that repression of telomerase in somatic cells has evolved as a tumor-suppressor adaptation in large, long-lived organisms. We tested whether regulation of telomerase activity coevolves with lifespan and body mass using comparative analysis of 15 rodent species with highly diverse lifespans and body masses. Here we show that telomerase activity does not coevolve with lifespan but instead coevolves with body mass: larger rodents repress telomerase activity in somatic cells. These results suggest that large body mass presents a greater risk of cancer than long lifespan, and large animals evolve repression of telomerase activity to mitigate that risk.

Sensory stimuli to the body are conveyed by the spinal cord to the primary somatosensory cortex. It has long been thought that dorsal column afferents of the spinal cord represent the main pathway for these signals, but the physiological and behavioural consequences of cutting the dorsal column have been reported to range from mild and transitory to marked. We have re-examined this issue by sectioning the dorsal columns in the cervical region and recording the responses to hand stimulation in the contralateral primary somatosensory cortex (area 3b). Following a complete section of the dorsal columns, neurons in area 3b become immediately and perhaps permanently unresponsive to hand stimulation. Following a partial section, the remaining dorsal column afferents continue to activate neurons within their normal cortical target territories, but after five or more weeks the area of activation is greatly expanded. After prolonged recovery periods of six months or more, the deprived hand territory becomes responsive to inputs from the face (which are unaffected by spinal cord section). Thus, area 3b of somatosensory cortex is highly dependent on dorsal spinal column inputs, and other spinal pathways do not substitute for the dorsal columns even after injury.

Comparative studies amongst extant species are one of the pillars of evolutionary neurobiology. In the 20th century, most comparative studies remained restricted to analyses of brain structure volume and surface areas, besides estimates of neuronal density largely limited to the cerebral cortex. Over the last 10 years, we have amassed data on the numbers of neurons and other cells that compose the entirety of the brain (subdivided into cerebral cortex, cerebellum, and rest of brain) of 39 mammalian species spread over 6 clades, as well as their densities. Here we provide that entire dataset in a format that is readily useful to researchers of any area of interest in the hope that it will foster the advancement of evolutionary and comparative studies well beyond the scope of neuroscience itself. We also reexamine the relationship between numbers of neurons, neuronal densities and body mass, and find that in the rest of brain, but not in the cerebral cortex or cerebellum, there is a single scaling rule that applies to average neuronal cell size, which increases with the linear dimension of the body, even though there is no single scaling rule that relates the number of neurons in the rest of brain to body mass. Thus, larger bodies do not uniformly come with more neurons - but they do fairly uniformly come with larger neurons in the rest of brain, which contains a number of structures directly connected to sources or targets in the body.