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Parkinson mouse
Parkinson
mouse
Doparnineneumn agenesis in Nwldeficient mice Zetterstrom, R.H. P: ;I s;ici~~ Z, 248-250 Parkinson disease is caused by a progressive degcncration and 10:;s of the dopamine-producing neurons of the midbrain. Very little is known about either the factors controlling the tievelopment of these cells or the factors that lead to their loss in Parkinson disease. Some clarification of this issue is obtained with the repolt by Zetterstrom et al. that the mouse orphan nuclear
hormone receptor NURRI (human homolog, NOT) plays a critical role in the embryonic development of dopamine-producing neurons. Nuts-1 expression was detected in the developing dopamine neurons of mice beginning at embryonic day 10.5, before any other known phenotypic markers for these cells. Homozygous Nurrl knockout mice failed to develop
Markers dreams are made of Fo1lowir.gcell fate in the living mouse embryo Zemicka-Goerz,M. el al. Deuehpneuf 124, 1133-1137 Zemicka-Goes marker longed
et al. describe
a cell
for b mammalian developmental biologists: a modified form of green fluorescent protein (MmGFP). which visibly marks selectable cell populations in living mouSe embryos without disrupting normal development. To generate MmGFP, mutations were introduced into the protein to improve its folding at 37°C and enhance its visibility by increasing its absorption of biue light. To follow the
lineage of proliferating cells during development, .stable expression of MmGFP in ES cells was achieved under the control of the human C~c2 promoter. in cuhure, proliferating ES cells from these cell lines visibly fluoresced, while those induced to exit the cell cycle and differentiate did not. To investigate whether MmGFP could act as an enduring cell marker, MmGFP mRNA was injected into a blastomere of a two-cellstage embryo. The authors were able
ABL and DNA damage Fuocrionaiiraenaion berween DNA-PKand ABLin response to DNAdamage Kharbanda,S. et RI. A’ntwe386, 732-735 The proto-oncogene ABL encodes a tyrosine kinase that has heen shown fo he involved in the cellular response to certa.n DNA damaging agents. including ionizing radiation. Previous studies have demcnstrdted that ABL has a role in activating ~53 and other key regulators of ce!lular proliferation after DNA damage, but the mechanism by which this occurs remains unclear. This paper provides the first evidence to suggest how ABL could be utilized by the cell to link a damage-recognition event and a signal cascade, leading either to cell-cycle arrest and repair of the damage, or to apoptotic cel1 death. lbing a co-immunoprecipitation strutegy. the authors have demonstrated an interaction between ABL and the DNAdependent protein kinase (DNA-OK), which was enhanced after cells had been exposed to ionizing radiation. This interaction between ABL and DNA-PK resulted in the phosphorylation and
partial activation of ABL kinase. Fkcdu.w DNA-PK is believed to aci as a sensor of DNA double-strand breaks (DSBs) in the cell, these results suggest that there is a simple mechanism for coupling the recognition of DSBs to cellular effectom. Additional experiments showed that activated (i.e. phosphotylated) ABL. in turn, phosphorylated DNA-PK, thereby inhibiting the association of DNA-PK with DNA and. hence, its kinase activity. Therefore, a negative
midbrain dopaminergic neurons and died within two days of birth, apparently as a result of a failure to suckle. Furthermore, adult heterozygote mice - otherwise apparently normal - had reduced striatal levels of dopamine, which suggests that Nurrl also plays a role in the maintenance of the dopaminergic neurons. While the discovery of the natural NLJRRX iigand wtil now be eagedy awaited, this work clearly identifies NURRl as an attractive candidate for pharmaceutical intervention in Parkinson disease, as well as other disorders involving dopamine?l erglc neurons.
to trace the progeny of this cell to the blastocyst stage of development by their visible fluorescence. To determine whether MmGFP-expressing ES cells could contribute to normal development and he u-aced in a living mouse embryo, aggregation chimeras were generated and expression of MmGFP was seen in proliferating cell populations in pre- and post-implantation embryos. When transplanted to foster
females, chimeric blastocysts and those injected with MmGFP ES cells delelaped to itrm and became healthy adult mice, suggesting that frequent examination of the emb,ryos by confocal microscopy did not interfere with nor6 mal development.
feedback loop might exist to prevent persisreence of the damage-induced signal. Taken together, these data suggest that subtle alterations in the availability and activity of ABL and DNA-PK could be ultimately responsible for determining the fate of cells which have suss tained DNA damage. Note added in proof Two additional papers have been published recently that demonstrate an interaction between ABL and ATM (the product of the gene defective in ataxla-telangiectasia) in response to DNA damage. See Baskaran, R. d al. A’alrrw 387. 516520: and Shafman. T. d al. hkztrtm 387, 520-523.
Monitor contributors this month Simon Whitfield. Jonathan Hodgkin, Leonard Guarente. Stephen Math@ Jane Alfred and Cath Green.
TIG JULY 1997 VOL. 13 No. 7
263
mouse
Doparnineneumn agenesis in Nwldeficient mice Zetterstrom, R.H. P: ;I s;ici~~ Z, 248-250 Parkinson disease is caused by a progressive degcncration and 10:;s of the dopamine-producing neurons of the midbrain. Very little is known about either the factors controlling the tievelopment of these cells or the factors that lead to their loss in Parkinson disease. Some clarification of this issue is obtained with the repolt by Zetterstrom et al. that the mouse orphan nuclear
hormone receptor NURRI (human homolog, NOT) plays a critical role in the embryonic development of dopamine-producing neurons. Nuts-1 expression was detected in the developing dopamine neurons of mice beginning at embryonic day 10.5, before any other known phenotypic markers for these cells. Homozygous Nurrl knockout mice failed to develop
Markers dreams are made of Fo1lowir.gcell fate in the living mouse embryo Zemicka-Goerz,M. el al. Deuehpneuf 124, 1133-1137 Zemicka-Goes marker longed
et al. describe
a cell
for b mammalian developmental biologists: a modified form of green fluorescent protein (MmGFP). which visibly marks selectable cell populations in living mouSe embryos without disrupting normal development. To generate MmGFP, mutations were introduced into the protein to improve its folding at 37°C and enhance its visibility by increasing its absorption of biue light. To follow the
lineage of proliferating cells during development, .stable expression of MmGFP in ES cells was achieved under the control of the human C~c2 promoter. in cuhure, proliferating ES cells from these cell lines visibly fluoresced, while those induced to exit the cell cycle and differentiate did not. To investigate whether MmGFP could act as an enduring cell marker, MmGFP mRNA was injected into a blastomere of a two-cellstage embryo. The authors were able
ABL and DNA damage Fuocrionaiiraenaion berween DNA-PKand ABLin response to DNAdamage Kharbanda,S. et RI. A’ntwe386, 732-735 The proto-oncogene ABL encodes a tyrosine kinase that has heen shown fo he involved in the cellular response to certa.n DNA damaging agents. including ionizing radiation. Previous studies have demcnstrdted that ABL has a role in activating ~53 and other key regulators of ce!lular proliferation after DNA damage, but the mechanism by which this occurs remains unclear. This paper provides the first evidence to suggest how ABL could be utilized by the cell to link a damage-recognition event and a signal cascade, leading either to cell-cycle arrest and repair of the damage, or to apoptotic cel1 death. lbing a co-immunoprecipitation strutegy. the authors have demonstrated an interaction between ABL and the DNAdependent protein kinase (DNA-OK), which was enhanced after cells had been exposed to ionizing radiation. This interaction between ABL and DNA-PK resulted in the phosphorylation and
partial activation of ABL kinase. Fkcdu.w DNA-PK is believed to aci as a sensor of DNA double-strand breaks (DSBs) in the cell, these results suggest that there is a simple mechanism for coupling the recognition of DSBs to cellular effectom. Additional experiments showed that activated (i.e. phosphotylated) ABL. in turn, phosphorylated DNA-PK, thereby inhibiting the association of DNA-PK with DNA and. hence, its kinase activity. Therefore, a negative
midbrain dopaminergic neurons and died within two days of birth, apparently as a result of a failure to suckle. Furthermore, adult heterozygote mice - otherwise apparently normal - had reduced striatal levels of dopamine, which suggests that Nurrl also plays a role in the maintenance of the dopaminergic neurons. While the discovery of the natural NLJRRX iigand wtil now be eagedy awaited, this work clearly identifies NURRl as an attractive candidate for pharmaceutical intervention in Parkinson disease, as well as other disorders involving dopamine?l erglc neurons.
to trace the progeny of this cell to the blastocyst stage of development by their visible fluorescence. To determine whether MmGFP-expressing ES cells could contribute to normal development and he u-aced in a living mouse embryo, aggregation chimeras were generated and expression of MmGFP was seen in proliferating cell populations in pre- and post-implantation embryos. When transplanted to foster
females, chimeric blastocysts and those injected with MmGFP ES cells delelaped to itrm and became healthy adult mice, suggesting that frequent examination of the emb,ryos by confocal microscopy did not interfere with nor6 mal development.
feedback loop might exist to prevent persisreence of the damage-induced signal. Taken together, these data suggest that subtle alterations in the availability and activity of ABL and DNA-PK could be ultimately responsible for determining the fate of cells which have suss tained DNA damage. Note added in proof Two additional papers have been published recently that demonstrate an interaction between ABL and ATM (the product of the gene defective in ataxla-telangiectasia) in response to DNA damage. See Baskaran, R. d al. A’alrrw 387. 516520: and Shafman. T. d al. hkztrtm 387, 520-523.
Monitor contributors this month Simon Whitfield. Jonathan Hodgkin, Leonard Guarente. Stephen Math@ Jane Alfred and Cath Green.
TIG JULY 1997 VOL. 13 No. 7
263