Cholesterol homeostasis in development: The role of Xenopus 7‐dehydrocholesterol reductase (Xdhcr7) in neural development

Abstract

7-dehydrocholesterol reductase (7-Dhcr) catalyses the final step in the pathway of cholesterol biosynthesis. Human patients with inborn errors of 7-Dhcr (Smith-Lemli-Opitz-Syndrome) have elevated serum levels of 7-dehydrocholesterol but low levels of cholesterol, which in phenotypical terms can result in growth retardation, craniofacial abnormalities including cleft palate, and reduced metal abilities. This study reports the isolation and molecular characterisation of 7-dehydrocholesterol reductase (Xdhcr7) from Xenopus laevis. During early embryonic development, the expression of Xdhcr7 is first of all spatially restricted to the Spemann's organizer and later to the notochord. In both tissues, Xdhcr7 is coexpressed with Sonic hedgehog (Shh), which itself is cholesterol-modified during autoproteolytic cleavage. Data from Xdhcr7 overexpression and knockdown experiments reveals that a tight control of cholesterol synthesis is particularly important for proper development of the central and peripheral nervous system.

Perinatal Outcomes After Statin Exposure During Pregnancy

“…Cholesterol synthesis is crucial for the development of both the central and peripheral nervous systems. [15][16][17] In rats, inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by simvastatin was found to significantly reduce fetal testosterone production. 18 However, to our knowledge, few studies have explored the association of maternal cholesterol reduction with neonatal outcomes, despite concerns regarding teratogenicity arising from animal models.…”

“…Cholesterol and its derivatives are considered essential components for fetal development, and they are involved in the synthesis of steroids and cell membranes. Cholesterol synthesis is crucial for the development of both the central and peripheral nervous systems . In rats, inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by simvastatin was found to significantly reduce fetal testosterone production .…”

More challenges ahead of DHCR7's role in Hh signaling

“…Recently, three isoforms of DHCR7 have been isolated in Xenopus, and splice variants RESPONSE Development 133, 3952-3953 (2006Development 133, 3952-3953 ( ) doi:10.1242 More challenges ahead of DHCR7's role in Hh signaling CORRESPONDENCE Development 133 (20) of DHCR7 in rats and mice have also been identified (Tadjuidje and Hollemann, 2006;Lee et al, 2002). Interestingly, the Xenopus isoforms do not display identical phenotypes when assayed by overexpression (Tadjuidje and Hollemann, 2006), raising the possibility that different forms of DHCR7 may display different activities.…”

“…Interestingly, the Xenopus isoforms do not display identical phenotypes when assayed by overexpression (Tadjuidje and Hollemann, 2006), raising the possibility that different forms of DHCR7 may display different activities. In light of the apparent dual function of DHCR7, it is tempting to speculate that different forms of DHCR7 are expressed in different tissues, and that these display different levels of reductase and Hh antagonistic activities.…”

Sterol carrier protein 2 regulates proximal tubule size in the Xenopus pronephric kidney by modulating lipid rafts

“…Mevinolin) disrupts signaling events mediated by lipid rafts (Klein et al, 1995; Taraboulos et al, 1995). They cause dramatic defects during embryonic development affecting signaling pathways like sonic hedgehog and Wnt (Cooper et al, 2003; Tadjuidje and Hollemann, 2006; Anderson et al, 2011; Reis et al, 2012). Similarly, mice lacking protein components of lipid rafts such as Caveolin-1 display a wide range of embryological defects (Drab et al, 2001; Razani et al, 2001; Zhao et al, 2002).…”