Astrocyte activation is suppressed in both normal and injured brain by FGF signaling.

In the brain, astrocytes are multifunctional cells that react to insults and contain damage. However, excessive or sustained reactive astrocytes can be deleterious to functional recovery or contribute to chronic inflammation and neuronal dysfunction. Therefore, astrocyte activation in response to damage is likely to be tightly regulated. Although factors that activate astrocytes have been identified, whether factors also exist that maintain astrocytes as nonreactive or reestablish their nonreactive state after containing damage remains unclear. By using loss- and gain-of-function genetic approaches, we show that, in the unperturbed adult neocortex, FGF signaling is required in astrocytes to maintain their nonreactive state. Similarly, after injury, FGF signaling delays the response of astrocytes and accelerates their deactivation. In addition, disrupting astrocytic FGF receptors results in reduced scar size without affecting neuronal survival. Overall, this study reveals that the activation of astrocytes in the normal and injured neocortex is not only regulated by proinflammatory factors, but also by factors such as FGFs that suppress activation, providing alternative therapeutic targets.

Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche.

Adult hypothalamic neurogenesis has recently been reported, but the cell of origin and the function of these newborn neurons are unknown. Using genetic fate mapping, we found that median eminence tanycytes generate newborn neurons. Blocking this neurogenesis altered the weight and metabolic activity of adult mice. These findings reveal a previously unreported neurogenic niche in the mammalian hypothalamus with important implications for metabolism.

Genetic approaches identify adult pituitary stem cells.

Adult tissues undergo continuous cell turnover in response to stress, damage, or physiological demand. New differentiated cells are generated from dedicated or facultative stem cells or from self-renewing differentiated cells. Here we describe a different stem cell strategy for tissue maintenance, distinct from that observed for dedicated or facultative stem cells. We report the presence of nestin-expressing adult stem cells in the perilumenal region of the mature anterior pituitary and, using genetic inducible fate mapping, demonstrate that they serve to generate subsets of all six terminally differentiated endocrine cell types of the pituitary gland. These stem cells, while not playing a significant role in organogenesis, undergo postnatal expansion and start producing differentiated progeny, which colonize the organ that initially entirely consisted of differentiated cells derived from embryonic precursors. This generates a mosaic organ with two phenotypically similar subsets of endocrine cells that have different origins and different life histories. These parallel but distinct lineages of differentiated cells in the gland may help the maturing organism adapt to changes in the metabolic regulatory landscape.

Mosaic removal of hedgehog signaling in the adult SVZ reveals that the residual wild-type stem cells have a limited capacity for self-renewal.

The Smoothened gene is necessary for cells to transduce hedgehog signaling. Although we and others have previously shown that embryonic removal of Smoothened in the neural tube results in a loss of stem cells from the postnatal subventricular zone, it was unclear whether this reflected a requirement for hedgehog signaling in the establishment or maintenance of the adult niche. Here, we have examined the consequences of conditional removal of Smoothened gene function within the subventricular zone of the adult neural stem cell niche. We observe that both proliferation and neurogenesis are compromised when hedgehog signaling is removed from subventricular zone stem cells. Moreover, even after a 10 month survival period, the stem cell niche fails to recover. It has been reported that the adult subventricular zone quickly rebounds from an antimitotic insult by increasing proliferation and replenishing the niche. During this recovery, it has been reported that hedgehog signaling appears to be upregulated. When mice in which hedgehog signaling in the subventricular zone has been strongly attenuated are given a similar antimitotic treatment, recovery is limited to the reduced level of proliferation and neurogenesis observed before the mitotic insult. Furthermore, the limited recovery that is observed appears to be largely restricted to the minority of neural stem cells that escape the conditional inactivation of Smoothened gene function. These results demonstrate that ongoing hedgehog signaling is required to maintain adult neural stem cells and that their ability to self-renew is limited.

Hedgehog signaling in the subventricular zone is required for both the maintenance of stem cells and the migration of newborn neurons.

We examined the postnatal consequences of removing Hedgehog signaling within the adult stem cell niche. Although at birth the subventricular zone appears normal in mice lacking Hedgehog signaling, by postnatal day 8 it is greatly impaired, and cell death is increased. In addition, both the quiescent B stem cell population and transit-amplifying C cells become depleted postnatally. In contrast, the A cell population expands precociously, mostly fails to migrate to the olfactory bulbs, and is ultimately also depleted by postnatal day 30. In vitro and in vivo analyses demonstrate that this failure in migration is a result of nonautonomous signaling, possibly caused by a reduction in Slit1 ligand in A cells. These results suggest that Hedgehog signaling is required for the maintenance of the B and C cell populations and indirectly for the migration of the neurons that are generated from the adult stem cell niche.

Differential regulation of Notch signal transduction in leukaemia and lymphoma cells in culture.

The transduction of Notch signal plays an intricate role in cell differentiation and pathogenesis of haematological malignancies as well as in certain congenital conditions. We found no genomic changes in either gene in 34 leukaemic samples and 25 leukaemia and lymphoma cell lines. The functionality of Notch signalling was tested using HES1 gene activation. We show that Notch signalling is differentially regulated in T-acute lymphoblastic leukaemia (ALL) and B-lymphoma cells. The Notch pathway is intact in a majority of B-lymphoma cell lines, but EBNA2, which mimics notch function, can occasionally activate the pathway. In contrast, the Notch pathway is constitutively active in T-ALL. This is the first demonstration of a distinction between B-lymphomas and T-cell leukaemias in the functioning of the Notch-signalling pathway. This might be related to their pathogenesis.

Allele frequency of two intragenic microsatellite loci of SEL1L gene in Northern Italian population.

Two cytosine-adenine (CA) repeats CAR/CAL and RepIN20 occur in the human SEL1L gene, which is regarded as a candidate gene for insulin-dependent diabetes mellitus (IDDM) and Grave's disease. We have characterized these repeats to determine if they might serve as effective microsatellite markers for linkage analysis to clarify whether SEL1L gene plays a role in the pathogenesis of these autoimmune diseases. The allele frequencies and average heterozygosity of the microsatellite repeats were analysed in 94 DNA samples from peripheral blood mononuclear (PBMC) cells from adults of Northern Italy. The average heterozygosity was 0.68 for CAR/CAL polymorphism and 0.85 for RepIN20. The size of PCR fragments of CAR/CAL ranged from 207-225 bp and the most frequent allele was 207 bp (40.4%). The size of the fragments of RepIN20 ranged from 237-255 bp and the most frequent allele was 249 bp (30.8%). In the light of the highly polymorphic nature of both microsatellites and their intragenic location in SEL1L gene, we suggest that they could provide a means for linkage analysis to clarify the potential role of SEL1L in conferring susceptibility to IDDM or Grave's disease.