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Stem cells and sperm cells – the GDNF connection
Genetic screens override investigators’ predilections and permit the internal logic of cells to point the way. Following this strategy, Chen et al.1 uncovered a possible role for lipid asymmetry in clathrin function in the late Golgi. Their starting point was the small GTPbinding protein ADP-ribosylation factor (ARF), which mediates assembly of COPI coats in the cis-Golgi and clathrin coats in the trans-Golgi. Yeast strains deleted for ARF1 survive (by virtue of a second less strongly expressed gene encoding ARF) but display defects in secretory kinetics and Golgi and endosome structure. The authors sought secondary mutations that would cause loss of viability in
their ARF1 deletion strain. The screen rounded up likely suspects, such as a temperature-sensitive allele of the gene encoding the clathrin heavy chain, but also an allele of DRS2, which encodes an integral membrane P-type ATPase. This enzyme appears to be an orthologue of mammalian ATPase II, a likely aminophospholipid translocase that flips phosphatidylserine and phosphatidylethanolamine to the cytoplasmic leaflet of lipid bilayers. Genetic analysis, cell-labelling studies and subcellular fractionation placed Drs2p in the late Golgi (rather than the plasma membrane as previously supposed). Moreover, deletion of DRS2 caused a deficiency in clathrin-coated vesicles
HEADLINES
Flipping for coats in late-Golgi membranes? and a lack of fenestration and tubular regions in Golgi membranes. Bilayer asymmetries of the type generated by aminophospholipid translocases are known to induce structures such as membrane tubules to form. Do features such as this facilitate the assembly of clathrin coats in the late Golgi? Such questions aside, the authors confess that a crucial next step is to confirm that Drs2p is in fact an aminophospholipid translocase. 1 Chen, C-Y. et al. (1999) Role of Drs2p, a P-type ATPase and potential aminophospholipid translocase, in yeast late Golgi function. J Cell Biol. 147, 1223–1236
Stem cells and sperm cells – the GDNF connection Eternal life, big business, ethical issues and cutting-edge research. Is this a clip from a Hollywood advertisement or a scientific journal? Stem cell researchers and readers of Science know that the latter is correct, for a recent issue of Science focused on the current, complex and costly issues in stem cell research. Stem cells are extraordinary in that they are eternally dividing and, if given the proper signals, can give rise to entire lineage of differentiated cells. Male gamete production is absolutely dependent upon stem cells for the copious sperm are short lived and must therefore be renewed constantly. In the seminiferous tubules, undifferentiated spermatogonia (stem cells) give rise to the differentiated spermatogonia, which ultimately develop into sperm. The signals that incite the undifferentiated spermatogonia to differentiate and the interaction between the gametes and the Sertoli cells
(somatic cells of the seminiferous tubule) are enigmatic. This relationship was investigated by Meng et al.1, who used transgenic mice to ask whether glial-derived neurotrophic factor (GDNF), a molecule secreted by the Sertoli cells, effects spermatogonia renewal and differentiation. Mice expressing low levels of GDNF are fertile yet have a greatly reduced sperm count owing to atrophic tubules, although the reason for atrophy was not explored. Transgenics overexpressing GDNF in the testis show an interesting phenotype that suggests that GDNF levels are a key signal for stem cell differentiation. Large clusters of undifferentiated spermatogonia are found in the testes of GDNF-overexpressing juvenile mice, and these clusters atrophy during puberty, resulting in sterile adults. Feeding the mice retinol, which stimulates differentiation of normal undifferentiated spermatogonia,
did not induce these cell clusters to differentiate but instead caused them to undergo apoptosis. Moreover, the cell clusters divided more frequently than controls, and older mice had a high rate of testicular tumours (albeit of uncharacterized nature). Taken together, these results suggest that the Sertoli cells, via their secretion of GDNF, regulate stem cell function. The finding that decreased GDNF levels result in testicular atrophy and that high GDNF leads to testicular tumour formation is an interesting lead for the big-business aspect of the stem cell field, for these cells are promising targets for therapeutic intervention for men suffering from infertility or testicular cancer. 1 Meng, X. (2000) Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287, 1489–1492
The silence of the aged We have all heard that old people can be easily confused, but here are two papers that could easily leave one confused about aging – especially as the papers actually deal with the process of transcriptional silencing. Part trends in CELL BIOLOGY (Vol. 9) May 1999
of the problem is that the two labs approach the problem from a different perspective. The bottom line is that a protein implicated both in silencing and in aging in yeast has been convincingly shown to use NAD as a
cofactor. With a little stretch, a connection is made between metabolism and aging in yeast, and, with another small leap, one might eventually explain the well-worn conundrum that increased metabolic rate in higher
179
their ARF1 deletion strain. The screen rounded up likely suspects, such as a temperature-sensitive allele of the gene encoding the clathrin heavy chain, but also an allele of DRS2, which encodes an integral membrane P-type ATPase. This enzyme appears to be an orthologue of mammalian ATPase II, a likely aminophospholipid translocase that flips phosphatidylserine and phosphatidylethanolamine to the cytoplasmic leaflet of lipid bilayers. Genetic analysis, cell-labelling studies and subcellular fractionation placed Drs2p in the late Golgi (rather than the plasma membrane as previously supposed). Moreover, deletion of DRS2 caused a deficiency in clathrin-coated vesicles
HEADLINES
Flipping for coats in late-Golgi membranes? and a lack of fenestration and tubular regions in Golgi membranes. Bilayer asymmetries of the type generated by aminophospholipid translocases are known to induce structures such as membrane tubules to form. Do features such as this facilitate the assembly of clathrin coats in the late Golgi? Such questions aside, the authors confess that a crucial next step is to confirm that Drs2p is in fact an aminophospholipid translocase. 1 Chen, C-Y. et al. (1999) Role of Drs2p, a P-type ATPase and potential aminophospholipid translocase, in yeast late Golgi function. J Cell Biol. 147, 1223–1236
Stem cells and sperm cells – the GDNF connection Eternal life, big business, ethical issues and cutting-edge research. Is this a clip from a Hollywood advertisement or a scientific journal? Stem cell researchers and readers of Science know that the latter is correct, for a recent issue of Science focused on the current, complex and costly issues in stem cell research. Stem cells are extraordinary in that they are eternally dividing and, if given the proper signals, can give rise to entire lineage of differentiated cells. Male gamete production is absolutely dependent upon stem cells for the copious sperm are short lived and must therefore be renewed constantly. In the seminiferous tubules, undifferentiated spermatogonia (stem cells) give rise to the differentiated spermatogonia, which ultimately develop into sperm. The signals that incite the undifferentiated spermatogonia to differentiate and the interaction between the gametes and the Sertoli cells
(somatic cells of the seminiferous tubule) are enigmatic. This relationship was investigated by Meng et al.1, who used transgenic mice to ask whether glial-derived neurotrophic factor (GDNF), a molecule secreted by the Sertoli cells, effects spermatogonia renewal and differentiation. Mice expressing low levels of GDNF are fertile yet have a greatly reduced sperm count owing to atrophic tubules, although the reason for atrophy was not explored. Transgenics overexpressing GDNF in the testis show an interesting phenotype that suggests that GDNF levels are a key signal for stem cell differentiation. Large clusters of undifferentiated spermatogonia are found in the testes of GDNF-overexpressing juvenile mice, and these clusters atrophy during puberty, resulting in sterile adults. Feeding the mice retinol, which stimulates differentiation of normal undifferentiated spermatogonia,
did not induce these cell clusters to differentiate but instead caused them to undergo apoptosis. Moreover, the cell clusters divided more frequently than controls, and older mice had a high rate of testicular tumours (albeit of uncharacterized nature). Taken together, these results suggest that the Sertoli cells, via their secretion of GDNF, regulate stem cell function. The finding that decreased GDNF levels result in testicular atrophy and that high GDNF leads to testicular tumour formation is an interesting lead for the big-business aspect of the stem cell field, for these cells are promising targets for therapeutic intervention for men suffering from infertility or testicular cancer. 1 Meng, X. (2000) Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287, 1489–1492
The silence of the aged We have all heard that old people can be easily confused, but here are two papers that could easily leave one confused about aging – especially as the papers actually deal with the process of transcriptional silencing. Part trends in CELL BIOLOGY (Vol. 9) May 1999
of the problem is that the two labs approach the problem from a different perspective. The bottom line is that a protein implicated both in silencing and in aging in yeast has been convincingly shown to use NAD as a
cofactor. With a little stretch, a connection is made between metabolism and aging in yeast, and, with another small leap, one might eventually explain the well-worn conundrum that increased metabolic rate in higher
179