Regulation of left-right patterning in mice by growth/differentiation factor-1

Abstract

The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of structurally related polypeptides that are capable of regulating cell growth and differentiation in a wide range of embryonic and adult tissues. Growth/differentiation factor-1 (Gdf-1, encoded by Gdf1) is a TGF-beta family member of unknown function that was originally isolated from an early mouse embryo cDNA library and is expressed specifically in the nervous systemin late-stage embryos and adult mice. Here we show that at early stages of mouse development, Gdfl is expressed initially throughout the embryo proper and then most prominently in the primitive node, ventral neural tube, and intermediate and lateral plate mesoderm. To examine its biological function, we generated a mouse line carrying a targeted mutation in Gdf1. Gdf1-/- mice exhibited a spectrum of defects related to left-right axis formation, including visceral situs inversus, right pulmonary isomerism and a range of cardiac anomalies. In most Gdf1-/- embryos, the expression of Ebaf (formerly lefty-1) in the left side of the floor plate and Leftb (formerly lefty-2), nodal and Pitx2 in the left lateral plate mesoderm was absent, suggesting that Gdf1 acts upstream of these genes either directly or indirectly to activate their expression. Our findings suggest that Gdf1 acts early in the pathway of gene activation that leads to the establishment of left-right asymmetry.

Man1, an inner nuclear membrane protein, regulates left–right axis formation by controlling nodal signaling in a node‐independent manner

“…We next examined the expression of Cerberus-like 2 (Cer2), growth differentiation factor 1 (Gdf1), and Wnt3a, which are all expressed in the perinodal region and are implicated in LR determination (Rankin et al, 2000;Marques et al, 2004;Nakaya et al, 2005). As shown in Figure 5G-J, the expression of Cerl2 and Gdf1 in the perinodal region did not change significantly in Man1 ⌬/⌬ mutants.…”

Nodal signalling and asymmetry of the nervous system

“…parapineal-independent asymmetries; see §5 and figures 3c and 4a) [52]. Also, symmetric Nodal signalling can induce isomerism in nonneural structures such as the adult rudiment of the sea urchin [53], the gonads of the female chick [54] and the murine lungs [55,56]. For the Hb of lampreys and catshark, it is remarkable that left-sided Nodal expression associates with contrasting morphological phenotypes, i.e.…”

Identification of a novel left–right asymmetrically expressed gene in the mouse belonging to the BPI/PLUNC superfamily

“…Dante is specifically expressed in the node at the early somite stage, but its role is currently unknown. Gdf1 -/-mice are known to exhibit a spectrum of defects related to L-R axis formation (Rankin et al, 2000). However, Gdf1 is expressed both in the node and the lateral plate, and it remains to be seen which expression domain is required for L-R patterning.…”

“…Alternatively, Nodal activity may be relayed somewhere between the node and the LPM. Dante (Pearce et al, 1999) and Gdf1 (Rankin et al, 2000) are asymmetrically expressed in the node of the mouse embryo, and they may play a role in transfer of asymmetric signals from the node to the LPM. Dante is specifically expressed in the node at the early somite stage, but its role is currently unknown.…”