肾管的形成
中文名称
通路描述
肾管起源于中间中胚层的肾原条，通过细胞向上皮转化的过程，响应来自体节和覆盖上皮外胚层的信号。最初，肾管在原肾囊内形成，原肾囊由肾管（此时为原肾管）和汇入其内的连接小管组成。随后，第二肾结构中肾囊在原肾囊的腹侧端形成，其中包含肾管的片段，即中肾管（也称为沃尔夫管），并连接有近端和远端小管，这些小管附于肾单位和血管性体节。中肾囊与尿囊融合并参与形成膀胱。随后，中肾囊形成并持续作为功能性的成年肾脏。中肾囊起源于中肾管腹侧端的尿生殖泡芽的启动，该过程由肾管与相邻的中肾囊间质之间的分子相互作用驱动。尿生殖泡芽随后分支，约一百万个肾单位（肾脏功能滤过单位）在中肾管尖端由尿生殖泡芽与中肾囊间质的相互作用形成。肾脏形成的位置由视黄酸梯度通过 HOXB4 同源框转录因子调节（基于小鼠胚胎数据，见 Preger-Ben Noon et al. 2009，综述 Marcotte et al. 2014）。PAX2、PAX8 和 LHX1 在中间中胚层形成早期表达。随后，LHX1 的表达被限制在发育中的肾原细胞中，并由 PAX2 和 PAX8 维持（基于小鼠同源物，见 Boualia et al. 2013）。在中肾管发育中，LHX1 与 PAX2 和 GATA3 协同作用，形成基于 LHX1 和 GATA3 相互激活的自我增强调节模块，驱动原肾囊和中肾管肾管的形成（基于小鼠同源物，见 Boualia et al. 2013，综述 Marcotte et al. 2014）。LHX1、GATA3、PAX2 和 PAX8 随后激活一系列参与肾管分化的基因，包括 EMX2、EVI1、ID4、PLAC8、WFDC2、PCDH19、Nephronectin (NPNT) 和受体酪氨酸激酶 RET（综述 Marcotte et al. 2014）。随后尿生殖泡芽的形成由中肾囊间质分泌的 GDNF 与 RET 之间的相互作用调节（基于小鼠同源物，见 Majumdar et al. 2003），以及中肾囊间质中的整合素 alpha8/beta1 (ITGA8) 与 NPNT 之间的相互作用（基于小鼠同源物，见 Brandenberger et al. 2001）。
英文描述
Chromatin modifications during the maternal to zygotic transition (MZT) Chromatin in the zygotic pronuclei transitions to a more open and accessible conformation by DNA demethylation and changes to histone modifications. As development proceeds through the cleavage stages to the blastocyst, chromatin continues to become more accessible until DNA methylation and a more restrictive chromatin conformation are re-established after implantation of the embryo in the uterus.
In the oocyte, H3K9me2 produced by EHMT2 (G9a, KMT1C) and H3K9me3 produced by SETDB1 (KMT1E) are transmitted to the female pronucleus of the zygote and protect maternal DNA from active demethylation (inferred from mouse zygotes in Zeng et al. 2019, reviewed in de Macedo et al. 2021). DPPA3 binds H3K9me2, preventing the 5-methylcytosine oxidase TET3 from being recruited to chromatin (inferred from mouse homologs in Nakamura et al. 2007, Wossidlo et al. 2011, Nakamura et al. 2012). DPPA3 also displaces UHRF1 from chromatin, preventing the maintenance DNA methylase DNMT1 from being recruited to chromatin and thus allowing passive DNA demethylation to occur in the female genome (inferred from mouse homologs in Funaki et al. 2014, Li et al. 2018, Du et al. 2019, Mulholland et al. 2020).
In the male pronucleus of the zygote, AICDA (AID) deaminates cytosine residues and long patch repair replaces the mismatches and adjacent 5-methylcytidine residues with cytidine (Santos et al. 2013, Franchini et al. 2014). After this initial demethylation, TET3 is recruited to chromatin by METTL23 and STGP4 (GSE) (inferred from mouse homologs in Hatanaka et al. 2017) where it oxidizes remaining 5-methylcytidine to 5-hydroxymethylcytidine, which is removed by base excision repair and replaced with cytidine (inferred from mouse homologs in Gu et al. 2011, Iqbal et al. 2011, Wossidlo et al. 2011, Santos et al. 2013, Amouroux et al. 2016, Hatanaka et al. 2017).
The repressive mark H3K27me3 decreases in 2-cell embryos near developmentally related genes (Xia et al. 2019). The H3K27me3 demethylases KDM6B (inferred from bovine embryos in Chung et al. 2017, Canovas et al. 2012) and KDM6A (inferred from mouse embryos in Bai et al. 2019) appear to play a role in the decrease of H3K27me3, as downregulation of them impairs H3K27me3 loss, zygotic genome activation, and embryonic development. Embryonic development also requires H3K36me3, a permissive mark located in transcribed gene bodies that is produced in the oocyte by SETD2 (inferred from mouse embryos in Xu et al. 2019).
In mouse oocytes, H3K4me3 occurs in unusually broad regions that span genes Dahl et al. 2016, Zhang et al. 2016). These broad regions persist in the zygote and into the 2-cell stage. In the late 2-cell stage the more usual patterns of H3K4me3 are established as sharp peaks of H3K4me3 near the transcription start sites and stop sites of genes. The histone methyltransferase KMT2B is at least partly responsible for establishing the broad regions of H3K4me3 in the oocyte and the histone demethylases KDM5B and KDM5A remove the broad H3K4me3 in the late 2-cell stage embryo (inferred from mouse homologs in Dahl et al. 2016, reviewed in Eckerseley-Maslin et al. 2018).
In human oocytes and zygotes, however, broad regions of H3K4me3 are not observed across genes but are located across distal, CpG-rich domains which have partial DNA methylation (Xia et al. 2019). At the 8-cell stage, expression of KDM5B increases and the H3K4me3 at the distal domains is lost as zygotic genome activation occurs, suggesting a role for KDM5B in loss of H3K4me3 (Xia et al. 2019).
In the oocyte, H3K9me2 produced by EHMT2 (G9a, KMT1C) and H3K9me3 produced by SETDB1 (KMT1E) are transmitted to the female pronucleus of the zygote and protect maternal DNA from active demethylation (inferred from mouse zygotes in Zeng et al. 2019, reviewed in de Macedo et al. 2021). DPPA3 binds H3K9me2, preventing the 5-methylcytosine oxidase TET3 from being recruited to chromatin (inferred from mouse homologs in Nakamura et al. 2007, Wossidlo et al. 2011, Nakamura et al. 2012). DPPA3 also displaces UHRF1 from chromatin, preventing the maintenance DNA methylase DNMT1 from being recruited to chromatin and thus allowing passive DNA demethylation to occur in the female genome (inferred from mouse homologs in Funaki et al. 2014, Li et al. 2018, Du et al. 2019, Mulholland et al. 2020).
In the male pronucleus of the zygote, AICDA (AID) deaminates cytosine residues and long patch repair replaces the mismatches and adjacent 5-methylcytidine residues with cytidine (Santos et al. 2013, Franchini et al. 2014). After this initial demethylation, TET3 is recruited to chromatin by METTL23 and STGP4 (GSE) (inferred from mouse homologs in Hatanaka et al. 2017) where it oxidizes remaining 5-methylcytidine to 5-hydroxymethylcytidine, which is removed by base excision repair and replaced with cytidine (inferred from mouse homologs in Gu et al. 2011, Iqbal et al. 2011, Wossidlo et al. 2011, Santos et al. 2013, Amouroux et al. 2016, Hatanaka et al. 2017).
The repressive mark H3K27me3 decreases in 2-cell embryos near developmentally related genes (Xia et al. 2019). The H3K27me3 demethylases KDM6B (inferred from bovine embryos in Chung et al. 2017, Canovas et al. 2012) and KDM6A (inferred from mouse embryos in Bai et al. 2019) appear to play a role in the decrease of H3K27me3, as downregulation of them impairs H3K27me3 loss, zygotic genome activation, and embryonic development. Embryonic development also requires H3K36me3, a permissive mark located in transcribed gene bodies that is produced in the oocyte by SETD2 (inferred from mouse embryos in Xu et al. 2019).
In mouse oocytes, H3K4me3 occurs in unusually broad regions that span genes Dahl et al. 2016, Zhang et al. 2016). These broad regions persist in the zygote and into the 2-cell stage. In the late 2-cell stage the more usual patterns of H3K4me3 are established as sharp peaks of H3K4me3 near the transcription start sites and stop sites of genes. The histone methyltransferase KMT2B is at least partly responsible for establishing the broad regions of H3K4me3 in the oocyte and the histone demethylases KDM5B and KDM5A remove the broad H3K4me3 in the late 2-cell stage embryo (inferred from mouse homologs in Dahl et al. 2016, reviewed in Eckerseley-Maslin et al. 2018).
In human oocytes and zygotes, however, broad regions of H3K4me3 are not observed across genes but are located across distal, CpG-rich domains which have partial DNA methylation (Xia et al. 2019). At the 8-cell stage, expression of KDM5B increases and the H3K4me3 at the distal domains is lost as zygotic genome activation occurs, suggesting a role for KDM5B in loss of H3K4me3 (Xia et al. 2019).
所含基因
39 个基因
AICDA
DPPA3
H2AFB1
H2AFJ
H2AFV
H2AFX
H2BFS
H3F3A
HIST1H2AB
HIST1H2AC
HIST1H2AD
HIST1H2AJ
HIST1H2BA
HIST1H2BB
HIST1H2BC
HIST1H2BD
HIST1H2BH
HIST1H2BJ
HIST1H2BK
HIST1H2BL
HIST1H2BM
HIST1H2BN
HIST1H2BO
HIST1H3A
HIST1H4
HIST2H2AA3
HIST2H2AC
HIST2H2BE
HIST2H3A
HIST3H2BB
KDM5A
KDM5B
KDM6A
KDM6B
METTL23
STPG4
TET3
UHRF1
UNG