Roles of GASP-1 and GDF-11 in Dental and Craniofacial Development

Abstract

Purpose Growth and differentiation factor-11 (GDF-11) is a TGF-β family member that plays important regulatory roles in development of multiple tissues which include axial skeletal patterning, palatal closure, and tooth formation. Proteins that have been identified as GDF-11 inhibitors include GDF-associated serum protein-1 (GASP-1) and GASP-2. Recently, we found that mice genetically engineered to lack both Gasp1 and Gdf11 have an increased frequency of cleft palate. The goal of this study was to investigate the roles of GDF-11 and its inhibitors, GASP-1 and GASP-2, during dental and craniofacial development and growth. Methods Mouse genetic studies were used in this study. Homozygous knockout mice for Gasp1 (Gasp1−/−) and Gasp2 (Gasp2−/−) were viable and fertile, but Gdf11 homozygous knockout (Gdf11−/−) mice died within 24 hours after birth. The effect of either Gasp1 or Gasp2 deletion in Gdf11−/− mice during embryogenesis was evaluated in Gasp1−/−;Gdf11−/− and Gasp2−/−;Gdf11−/− mouse embryos at 18.5 days post-coitum (E18.5). For the analysis of adult tissues, we used Gasp1−/−;Gdf11+/− and Gasp2−/−;Gdf11+/− mice to evaluate the potential haploinsufficiency of Gdf11 in Gasp1−/− and Gasp2−/− mice. Results Although Gasp2 expression decreased after E10.5, Gasp1 expression was readily detected in various ectodermal tissues at E17.5, including hair follicles, epithelium in nasal cavity, retina, and developing tooth buds. Interestingly, Gasp1−/−;Gdf11−/− mice had abnormal formation of lower incisors: tooth buds for lower incisors were under-developed or missing. Although Gdf11+/− mice were viable and had mild transformations of the axial skeleton, no specific defects in the craniofacial development have been observed in Gdf11+/− mice. However, loss of Gasp1 in Gdf11+/− mice occasionally resulted in small and abnormally shaped auricles. Conclusions These findings suggest that both GASP-1 and GDF-11 play important roles in dental and craniofacial development both during embryogenesis and in adult tissues.

TGF-β Family Signaling in Epithelial Differentiation and Epithelial–Mesenchymal Transition

“…GDF-11/BMP-11, a distant member of the TGF-b family, has been studied for its role in craniofacial development (Lee and Lee 2015). The binding of GDF-11 to its receptors is inhibited by the extracellular GDF-associated serum protein 1 (GASP1) (Lee and Lee 2013).…”

“…The binding of GDF-11 to its receptors is inhibited by the extracellular GDF-associated serum protein 1 (GASP1) (Lee and Lee 2013). Tooth buds start expressing GASP1 before embryonic age of E17.5, and mice with loss-of-function mutations in both the Gdf11 and Gasp1 genes show enhanced cleft palate and abnormal incisors in the lower mandible (Lee and Lee 2015). The incisor defect is due to lack of proliferation and differentiation in the tooth buds for these specific incisors only.…”

WFIKKN1 and WFIKKN2: “Companion” proteins regulating TGFB activity

“…The double KO mice Fst-/-; Wfikkn1-/-exhibit more skeletal defects than single gene inactivated mice suggesting a redundant function of these proteins. Further, WFIKKN2-/-; Gdf11-/-mice had abnormal formation of lower incisors [74].…”

Фактор Диференціації Росту 11: Загальнобіологічні Властивості, Метаболічні Ефекти Та Можлива Патофізіологічна Роль При Артеріальній Гіпертензії, Ожирінні, Цукровому Діабеті Та Залежній Від Віку Патології (Огляд Літератури)

“…В дослідженнях було ідентифіковано декілька білків, що зв'язують MSTN і GDF11, включаючи GDF-асоційовані сироваткові білки 1 і 2 (GASP1 і GASP2), які здатні пригнічувати активність цих лігандів. Автори ще декількох досліджень показують, що GASP1 і GASP2 діють, блокуючи початкову молекулярну сигнальну подію, а саме зв'язування ліганду з рецептором типу II [62][63][64]. Дослідники демонструють, що миші, у яких відсутні GASP1 і GASP2, мають фенотип, який характеризується гіперактивністю білків, у тому числі GDF11.…”

“…Всі ці дані свідчать про те, що як GASP-1, так і GASP-2 є важливими модуляторами активності GDF11 і MSTN in vivo. Крім цього, отримані дані, що ці сигнальні молекули беруть участь у краніофарингіальному диференціюванні та важливі за умов несприятливого перебігу одонтологічних захворювань [62]. [56].…”