Nail- patella syndrome (NPS) is an autosomal dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and nephro pathy. Recently, it was shown that NPS is the result of hete...Nail- patella syndrome (NPS) is an autosomal dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and nephro pathy. Recently, it was shown that NPS is the result of heterozygous mutations i n the LIM- homeodomain gene, LMX1B. Subsequently, many mutations of the LMX1B g ene have been reported in NPS patients. However, functional analyses of the muta nt proteins have been performed in only a few mutations. Furthermore, the mechan isms of dominant inheritance in humans have not been established. In the present study, we analyzed the LMX1B gene in three Japanese patients with NPS and ident ified two novel mutations, 6 nucleotide deletion (Δ 246N 247Q) and V242L. These two mutations are located in the homeodomain of LMX1B. Functional analyses of t he LMX1B mutants revealed that these mutants had diminished transcriptional activity and had lost DNA binding ability. Furthermore, we demonstrated that each mutant did not manifest a dominant- negative effect on the transcriptional activity of wild- type LMX1B. These results suggested that NPS is caused by lo ss- of- function mutations of LMX1B, and haploin sufficiency of LMX1B should b e the predominant pathogenesis of NPS in humans.展开更多
Isolation rearing(IR) enhances aggressive behavior, and the central serotonin(5-hydroxytryptamine,5-HT) system has been linked to IR-induced aggression.However, whether the alteration of central serotonin is the cause...Isolation rearing(IR) enhances aggressive behavior, and the central serotonin(5-hydroxytryptamine,5-HT) system has been linked to IR-induced aggression.However, whether the alteration of central serotonin is the cause or consequence of enhanced aggression is still unknown. In the present study, using mice deficient in central serotonin Tph2-/-and Lmx1 b-/-, we examined the association between central serotonin and aggression with or without social isolation. We demonstrated that central serotonergic neurons are critical for the enhanced aggression after IR. 5-HT depletion in wild-type mice increased aggression. On the other hand, application of 5-HT in Lmx1 b-/-mice inhibited the enhancement of aggression under social isolation conditions. Dopamine was downregulated in Lmx1 b-/-mice. Similar to 5-HT, L-DOPA decreased aggression in Lmx1 b-/-mice. Our results linkthe serotoninergic system directly to aggression and this may have clinical implications for aggression-related human conditions.展开更多
文摘Nail- patella syndrome (NPS) is an autosomal dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and nephro pathy. Recently, it was shown that NPS is the result of heterozygous mutations i n the LIM- homeodomain gene, LMX1B. Subsequently, many mutations of the LMX1B g ene have been reported in NPS patients. However, functional analyses of the muta nt proteins have been performed in only a few mutations. Furthermore, the mechan isms of dominant inheritance in humans have not been established. In the present study, we analyzed the LMX1B gene in three Japanese patients with NPS and ident ified two novel mutations, 6 nucleotide deletion (Δ 246N 247Q) and V242L. These two mutations are located in the homeodomain of LMX1B. Functional analyses of t he LMX1B mutants revealed that these mutants had diminished transcriptional activity and had lost DNA binding ability. Furthermore, we demonstrated that each mutant did not manifest a dominant- negative effect on the transcriptional activity of wild- type LMX1B. These results suggested that NPS is caused by lo ss- of- function mutations of LMX1B, and haploin sufficiency of LMX1B should b e the predominant pathogenesis of NPS in humans.
基金supported by the National Natural Science Foundation of China (81425009, 31630028, 91632305, 30950030, 31170988, and 81671044)the National Basic Research Development Program (973 Program) of China (2009CB522002)
文摘Isolation rearing(IR) enhances aggressive behavior, and the central serotonin(5-hydroxytryptamine,5-HT) system has been linked to IR-induced aggression.However, whether the alteration of central serotonin is the cause or consequence of enhanced aggression is still unknown. In the present study, using mice deficient in central serotonin Tph2-/-and Lmx1 b-/-, we examined the association between central serotonin and aggression with or without social isolation. We demonstrated that central serotonergic neurons are critical for the enhanced aggression after IR. 5-HT depletion in wild-type mice increased aggression. On the other hand, application of 5-HT in Lmx1 b-/-mice inhibited the enhancement of aggression under social isolation conditions. Dopamine was downregulated in Lmx1 b-/-mice. Similar to 5-HT, L-DOPA decreased aggression in Lmx1 b-/-mice. Our results linkthe serotoninergic system directly to aggression and this may have clinical implications for aggression-related human conditions.
