Kossel Clara-Sophie, Wahlbuhl Mandy, Schuepbach-Mallepell Sonia, Park Jung, Kowalczyk-Quintas Christine, Seeling Michaela, von der Mark Klaus, Schneider Pascal, Schneider Holm
Department of Pediatrics, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Center for Ectodermal Dysplasias, University Hospital Erlangen, Erlangen, Germany.
Front Genet. 2021 Aug 11;12:709736. doi: 10.3389/fgene.2021.709736. eCollection 2021.
X-linked hypohidrotic ectodermal dysplasia with the cardinal symptoms hypodontia, hypotrichosis and hypohidrosis is caused by a genetic deficiency of ectodysplasin A1 (EDA1). Prenatal EDA1 replacement can rescue the development of skin appendages and teeth. mice, a natural animal model of EDA1 deficiency, additionally feature a striking kink of the tail, the cause of which has remained unclear. We studied the origin of this phenomenon and its response to prenatal therapy. Alterations in the distal spine could be noticed soon after birth, and kinks were present in all mice by the age of 4 months. Although their vertebral bones frequently had a disorganized epiphyseal zone possibly predisposing to fractures, cortical bone density was only reduced in vertebrae of older mice and even increased in their tibiae. Different availability of osteoclasts in the spine, which may affect bone density, was ruled out by osteoclast staining. The absence of hair follicles, a well-known niche of epidermal stem cells, and much lower bromodeoxyuridine uptake in the tail skin of 9-day-old mice rather suggest the kink being due to a skin proliferation defect that prevents the skin from growing as fast as the skeleton, so that caudal vertebrae may be squeezed and bent by a lack of skin. Early postnatal treatment with EDA1 leading to delayed hair follicle formation attenuated the kink, but did not prevent it. mice born after prenatal administration of EDA1, however, showed normal tail skin proliferation, no signs of kinking and, interestingly, a normalized vertebral bone density. Thus, our data prove the causal relationship between EDA1 deficiency and kinky tails and indicate that hair follicles are required for murine tail skin to grow fast enough. Disturbed bone development appears to be partially pre-determined and can be counteracted by timely EDA1 replacement, pointing to a role of EDA1 also in osteogenesis.
X连锁少汗型外胚层发育不良的主要症状为牙齿发育不全、毛发稀少和出汗减少，是由外胚层发育不良蛋白A1（EDA1）的基因缺陷引起的。产前给予EDA1可挽救皮肤附属器和牙齿的发育。EDA1缺陷的天然动物模型小鼠，尾巴还有明显的扭结，其原因尚不清楚。我们研究了这种现象的起源及其对产前治疗的反应。出生后不久就能注意到远端脊柱的改变，到4个月大时，所有小鼠都出现了扭结。虽然它们的椎骨经常有排列紊乱的骨骺区，可能易发生骨折，但皮质骨密度仅在老年小鼠的椎骨中降低，在它们的胫骨中甚至增加。破骨细胞染色排除了脊柱中破骨细胞可用性不同可能影响骨密度的因素。毛囊是表皮干细胞的一个众所周知的微环境，9日龄小鼠尾巴皮肤中溴脱氧尿苷摄取量低得多，这表明扭结是由于皮肤增殖缺陷导致皮肤生长速度不如骨骼快，从而使尾椎可能因缺乏皮肤而受到挤压和弯曲。出生后早期用EDA1治疗导致毛囊形成延迟，减轻了扭结，但未能预防。然而，产前给予EDA1后出生的小鼠尾巴皮肤增殖正常，没有扭结迹象，有趣的是，椎骨骨密度也恢复正常。因此，我们的数据证明了EDA1缺陷与扭结尾巴之间的因果关系，并表明毛囊是小鼠尾巴皮肤快速生长所必需的。骨骼发育紊乱似乎部分是预先确定的，及时给予EDA1可以抵消这种紊乱，这表明EDA1在骨生成中也起作用。
