Research progress on the mechanism of dura mater in the growth and development of skull/meninges/brain tissue system

doi:10.11958/20240842

Abstract

Abstract:

Dura mater is a tough collagen connective tissue attached to inner surface of skull and wrapped around brain. As a buffer bridge between brain tissue and skull, its physiological function and role in skull development and repair have always been a focus of research. Recent studies have found that dura mater not only directly participates in skull development during skull growth, but also secretes a variety of cytokines that control the development of central nervous system. There are abundant material exchange and cell communication between the two. This article reviews the role of dura in development and repair of skull, and provides clues for further discovery of the relevant mechanisms of dura in development and repair of skull.

Key words: dura mater, skull development, skull injury repair

CLC Number:

R651.1+9

Figures/Tables 4

References 59

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细胞因子	调控方式	影响方式
FOXC1	激活/基因突变	硬脑膜发育的关键调控因子，FOXC1及其突变体的表达水平对顶部的硬脑膜具有高度的调控特异性^[15]；FOXC1突变后大脑顶侧不能形成蛛网膜、硬脑膜和颅骨^[16]。
FOXC1^ch/ch	基因突变	FOXC1的突变体，硬脑膜中FOXC1^ch/ch导致脑膜间充质干细胞（MSCs）在细胞排布上异常紧密的相互贴合，致使硬脑膜发育缺陷^[15?-17]。
FGF	激活/分化	形成神经胶质限制蛋白的基底膜（BM）蛋白的主要来源，直接调节骨化中心的形成^[18]，FGF亚型簇M1与软脑膜发育相关，亚型簇M3与蛛网膜发育相关，亚型簇M4与硬脑膜发育相关^[4]。
FAK	机械力负荷	FAK主要参与颅骨的发育过程，与维持颅腔和大气压压力差值密切相关，在维持硬脑膜结构完整性上起关键作用^[19-20]。
BMP	激活/去磷酸化/ 基因突变	与软脑膜发育关系密切，核心核因子Smad4调控皮质层的形成，参与皮质神经元的迁移^[21]；亚型BMP-2与静脉血管建立、亚型BMP-4与胶体、亚型BMP-5与后部脑膜、亚型BMP-7与皮质的生成发育有关^[22-23]。
Wnt/β-catenin	激活/敲除	当直接激活或移除β-catenin时，Wnt/β-catenin通路会导致外侧的脑膜发育不良与颅骨缺损^[4]；颅骨和非成骨性MSCs转化为软骨^[24]。
Twist1	基因缺失	维持硬脑膜与颅骨缝线处细胞保持低分化活性^[17]；Twist1缺失会导致部分硬脑膜缺损和蛛网膜下腔及颅缝的过早闭锁，限制大脑的发育，发生小儿狭颅症^[25]。
TGF-β	基因缺失	TGF-β/Smad2/3信号转导通路与脑膜形成与发育密切相关，当胚胎中缺失关键调节因子TGF-β2，前脑脑膜和硬脑膜外膜不能发育^[26]；在胚胎的早期阶段就被没有增殖能力的细胞所取代，在胚胎后期还会表现出颅骨与脑组织缺损^[27]。
Runx2	激活/异二聚化	诱导成骨细胞增殖、成骨前细胞向成骨后分化^[17]；维持颅骨缝线处开放和骨祖细胞（osteoprogenitor cell，OPC）库的数量与干性^[28-29]。
RA	激活	参与皮质神经和脑血管发育^[17]。

细胞因子	调控方式	影响方式
FOXC1	激活/基因突变	硬脑膜发育的关键调控因子，FOXC1及其突变体的表达水平对顶部的硬脑膜具有高度的调控特异性^[15]；FOXC1突变后大脑顶侧不能形成蛛网膜、硬脑膜和颅骨^[16]。
FOXC1^ch/ch	基因突变	FOXC1的突变体，硬脑膜中FOXC1^ch/ch导致脑膜间充质干细胞（MSCs）在细胞排布上异常紧密的相互贴合，致使硬脑膜发育缺陷^[15?-17]。
FGF	激活/分化	形成神经胶质限制蛋白的基底膜（BM）蛋白的主要来源，直接调节骨化中心的形成^[18]，FGF亚型簇M1与软脑膜发育相关，亚型簇M3与蛛网膜发育相关，亚型簇M4与硬脑膜发育相关^[4]。
FAK	机械力负荷	FAK主要参与颅骨的发育过程，与维持颅腔和大气压压力差值密切相关，在维持硬脑膜结构完整性上起关键作用^[19-20]。
BMP	激活/去磷酸化/ 基因突变	与软脑膜发育关系密切，核心核因子Smad4调控皮质层的形成，参与皮质神经元的迁移^[21]；亚型BMP-2与静脉血管建立、亚型BMP-4与胶体、亚型BMP-5与后部脑膜、亚型BMP-7与皮质的生成发育有关^[22-23]。
Wnt/β-catenin	激活/敲除	当直接激活或移除β-catenin时，Wnt/β-catenin通路会导致外侧的脑膜发育不良与颅骨缺损^[4]；颅骨和非成骨性MSCs转化为软骨^[24]。
Twist1	基因缺失	维持硬脑膜与颅骨缝线处细胞保持低分化活性^[17]；Twist1缺失会导致部分硬脑膜缺损和蛛网膜下腔及颅缝的过早闭锁，限制大脑的发育，发生小儿狭颅症^[25]。
TGF-β	基因缺失	TGF-β/Smad2/3信号转导通路与脑膜形成与发育密切相关，当胚胎中缺失关键调节因子TGF-β2，前脑脑膜和硬脑膜外膜不能发育^[26]；在胚胎的早期阶段就被没有增殖能力的细胞所取代，在胚胎后期还会表现出颅骨与脑组织缺损^[27]。
Runx2	激活/异二聚化	诱导成骨细胞增殖、成骨前细胞向成骨后分化^[17]；维持颅骨缝线处开放和骨祖细胞（osteoprogenitor cell，OPC）库的数量与干性^[28-29]。
RA	激活	参与皮质神经和脑血管发育^[17]。

组织/细胞	作用时期	调控方式与成骨特点
硬脑膜	3个时期	颅骨发育起始位，调节颅骨发育的转录因子，骨基质蛋白和成骨细胞的生态位^[4,17]。
SOM	胚胎期	颅骨形成位点，增殖分化OPC^[17,31]。
OPC	胚胎期	成骨细胞增殖分化的祖细胞^[17,37]。
中胚层细胞	胚胎期	以膜内骨化的方式促进颅骨穹窿的发育和顶端扩张，分化顶骨和枕骨^[38-39]。
神经嵴细胞	胚胎期	以软骨内成骨的方式促进颅底及附近颅面骨的发育，以膜内骨化促进额骨发育^[38-39]。

组织/细胞	作用时期	调控方式与成骨特点
硬脑膜	3个时期	颅骨发育起始位，调节颅骨发育的转录因子，骨基质蛋白和成骨细胞的生态位^[4,17]。
SOM	胚胎期	颅骨形成位点，增殖分化OPC^[17,31]。
OPC	胚胎期	成骨细胞增殖分化的祖细胞^[17,37]。
中胚层细胞	胚胎期	以膜内骨化的方式促进颅骨穹窿的发育和顶端扩张，分化顶骨和枕骨^[38-39]。
神经嵴细胞	胚胎期	以软骨内成骨的方式促进颅底及附近颅面骨的发育，以膜内骨化促进额骨发育^[38-39]。

基因	作用时期	调控方式与成骨特点
FOXC1	胚胎期	FOXC1与Runx2增强子及其两个启动子结合直接促进 Runx2 表达，促进成骨分化^[15-16]；FOXC1过表达促进钙结节形成^[17]。
RA	胚胎期	高水平的全反式维甲酸RA拮抗Wnt信号，抑制OPC形成前成骨细胞^[40]。
GATA4	婴儿期与青春期前	与FOXC1相互作用调节Runx2、OCN等成骨基因表达，FOXC1增强子可上调表达量；维持成年骨表型，敲除成骨细胞中的GATA4会导致骨小梁丢失^[41-42]。
RAB23	胚胎期	FGF和经典刺狸蛋白（Hh）/GLI1信号转导通路的上游负调节因子^[30]，维持胚胎期颅缝通畅，参与早期成骨；基因突变后OPC异常增殖和成骨增加，颅缝的过早融合导致Carpenter综合征（carpenter syndrome，CRPT）^[43]。
BMP	3个时期	亚型BMP-2促进矿化结节的形成和成骨分化；亚型BMP-4促进骨骼发育、重建和骨折愈合；亚型BMP-5促进骨折和软组织愈合；亚型BMP-7促进软骨形成；亚型BMP-9诱导成骨分化能力最强^[21?-23,44]。
FGF	3个时期	FGF-2通过丝裂原活化蛋白激酶（MAPK）通路激活和磷酸化股骨核心结合因子-a1（Cbfa1）/ Runx2，降低Wnt通路轴抑制蛋白2（axis inhibition protein 2，AXIN2）的活性；FGF9驱动软骨内骨化，基因突变后骨小梁形成增加和骨吸收减少，导致后额叶颅缝早闭^[18]；FGF信号转导的下游靶标SRY（sex determination region of Y chromosome）相关基因家族Sox2拮抗β-catenin信号通路导致顶骨变薄^[45]。
Wnt通路	3个时期	经典的Wnt通路主要控制细胞增殖，而非经典的Wnt通路调节细胞极性和介导神经嵴细胞与近轴中胚层细胞迁移；促进OPC增殖分化成骨基因^[46]；Wntless/Gpr177参与颅骨形成^[17]。
Prx1	婴儿期	在MSCs中表达，参与颅缝处骨生成与颅面骨生成^[30]；促进2周岁之前失状缝处临界骨缺损处骨组织内源性再生^[47]。
Runx2	3个时期	诱导脑膜缝线MSCs的增殖、成骨细胞分化和骨形成的主要因子^[17]；以剂量和时间依赖性刺激骨钙素 mRNA 启动子活性以抑制Twist1活性^[25]。
Twist1	3个时期	Twist1-E-蛋白异二聚体激活中胚层和神经嵴细胞的分化，Twist1同型二聚体将干细胞维持在祖细胞状态，并阻断进入内胚层谱系^[28]；Twist1可刺激FGF激活，与Runx2异二聚化，抑制其与DNA结合，抑制成骨；单倍体功能不全引起颅缝早闭^[48]。
Gli1	婴儿期与青春期前和损伤后	参与产生成人颅面骨，骨损伤后被激活，表达量减少引起颅缝早闭与颅骨生长停滞^[49]；缝线内Gli1+MSC的分化受成骨前沿细胞分泌的印度刺狸因子（Indian hedgehog，IHH）调节^[50]。
FAK	婴儿期与青春期前	通过PI3K通路、MAPK通路和ERK通路调节成骨基因表达；增强Wnt / β-catenin信号通路，促进成骨细胞、祖细胞增殖和分化^[19-20]。
Sp7	婴儿期与青春期前	调节颅面骨增殖、分化和活性；促进骨矿化^[37]。
COL1A1	青春期前	骨基质蛋白基因，参与骨量和骨脆性的调节，COL1A1通过FGFR2上调破骨细胞活性，导致小梁骨质丢失^[25]；突变导致I型胶原蛋白突变，导致成骨不全症（osteogenesis imperfecta，OI）^[51]。
OCN	婴儿期与青春期前	调节骨基质中的磷灰石晶体平行胶原纤维排列，增加新生骨强度^[25,32]。
PSC	正常发育和损伤后	颅骨正常发育和颅骨损伤后分化成骨细胞；表达量下降会导致颅骨发育不良和矿化不足，以及颅缝线扩大^[52]。