Chordin and noggin promote organizing centers of forebrain development in the mouse

Abstract

In this study we investigate the roles of the organizer factors chordin and noggin, which are dedicated antagonists of the bone morphogenetic proteins(BMPs), in formation of the mammalian head. The mouse chordin and noggin genes(Chrd and Nog) are expressed in the organizer (the node) and its mesendodermal derivatives, including the prechordal plate, an organizing center for rostral development. They are also expressed at lower levels in and around the anterior neural ridge, another rostral organizing center. To elucidate roles of Chrd and Nog that are masked by the severe phenotype and early lethality of the double null, we have characterized embryos of the genotype Chrd-/-;Nog+/-. These animals display partially penetrant neonatal lethality, with defects restricted to the head. The variable phenotypes include cyclopia,holoprosencephaly, and rostral truncations of the brain and craniofacial skeleton. In situ hybridization reveals a loss of SHH expression and signaling by the prechordal plate, and a decrease in FGF8 expression and signaling by the anterior neural ridge at the five-somite stage. DefectiveChrd-/-;Nog+/- embryos exhibit reduced cell proliferation in the rostral neuroepithelium at 10 somites, followed by increased cell death 1 day later. Because these phenotypes result from reduced levels of BMP antagonists, we hypothesized that they are due to increased BMP activity. Ectopic application of BMP2 to wild-type cephalic explants results in decreased FGF8 and SHH expression in rostral tissue, suggesting that the decreased expression of FGF8 and SHH observed in vivo is due to ectopic BMP activity. Cephalic explants isolated from Chrd;Nog double mutant embryos show an increased sensitivity to ectopic BMP protein, further supporting the hypothesis that these mutants are deficient in BMP antagonism. These results indicate that the BMP antagonists chordin and noggin promote the inductive and trophic activities of rostral organizing centers in early development of the mammalian head.

Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells

“…These organoids enriched well for cortical fates similar to Triple-i organoids, although they did not restrict posterior identity as firmly as those under Triple-i. These findings manifest the established instrumental role of BMP inhibition in the acquisition of anterior fates 37 .…”

In Vitro Osteoinductivity Assay of Hydroxylapatite Scaffolds, Obtained with Biomorphic Transformation Processes, Assessed Using Human Adipose Stem Cell Cultures

“…In agreement with this result, our data show the up-regulation of ALPL gene expression in hASCs grown on B-HA scaffold. Animal models have indicated that the BMP-antagonist chordin (CHRD) and Noggin promote inductive and trophic activities in rostral organizing centers during early development of the mammalian head [22]. In our study, SMAD3 and TGFB3 were up-regulated in hASCs grown on B-HA scaffolds compared to the control group represented by TCPS.…”

The Emerging Roles of the Cephalic Neural Crest in Brain Development and Developmental Encephalopathies

“…One, active in the early embryo at E1.5 -2, is located in the pre-chordal plate (PCP) and produces Bmp7; the other, located in the prosencephalic neuroepithelium and surface ectoderm, produces Bmp4 from E2 [102]. Factors expressed in the Spemann organizer, Chordin and Noggin, antagonists of Bmps, are involved in the control of forebrain development in the mouse [103,104]. However, CNC cells, during their migration, are a source of Bmps antagonistic factors, notably Gremlin and Noggin [105,106].…”