LIM homeobox transcription factors integrate signaling events that control three-dimensional limb patterning and growth

Abstract

Vertebrate limb development is controlled by three signaling centers that regulate limb patterning and growth along the proximodistal (PD),anteroposterior (AP) and dorsoventral (DV) limb axes. Coordination of limb development along these three axes is achieved by interactions and feedback loops involving the secreted signaling molecules that mediate the activities of these signaling centers. However, it is unknown how these signaling interactions are processed in the responding cells. We have found that distinct LIM homeodomain transcription factors, encoded by the LIM homeobox(LIM-HD) genes Lhx2, Lhx9 and Lmx1b integrate the signaling events that link limb patterning and outgrowth along all three axes. Simultaneous loss of Lhx2 and Lhx9 function resulted in patterning and growth defects along the AP and the PD limb axes. Similar, but more severe, phenotypes were observed when the activities of all three factors, Lmx1b, Lhx2 and Lhx9, were significantly reduced by removing their obligatory co-factor Ldb1. This reveals that the dorsal limb-specific factor Lmx1b can partially compensate for the function of Lhx2 and Lhx9 in regulating AP and PD limb patterning and outgrowth. We further showed that Lhx2and Lhx9 can fully substitute for each other, and that Lmx1bis partially redundant, in controlling the production of output signals in mesenchymal cells in response to Fgf8 and Shh signaling. Our results indicate that several distinct LIM-HD transcription factors in conjunction with their Ldb1 co-factor serve as common central integrators of distinct signaling interactions and feedback loops to coordinate limb patterning and outgrowth along the PD, AP and DV axes after limb bud formation.

Modularity of CHIP/LDB transcription complexes regulates cell differentiation

“…48 a similar function was suggested for LDB1 in intestinal crypts 49 and for LDB1, 50 and LHX2, 51 in hematopoiesis. specifically, in hematopoiesis, LDB1 has a critical role in the maintenance of fetal and adult hematopoietic stem cells and of cells downstream of them in the erythroid lineage.…”

Transcriptional components of anteroposterior positional information during zebrafish fin regeneration

“…Second, as mentioned above, a rich field of embryonic limb development has detailed the relationship between transcription factors and AP skeletal patterning (Qu et al, 1997;Charité et al, 2000;Fernandez-Teran et al, 2000;Zákány et al, 2004;Tzchori et al, 2009;Galli et al, 2010;Sheth et al, 2012). Third, our dataset revealed many examples of developmental transcription factors with expression differences along the AP axis.…”

“…; *P<0.05, **P<0.005, Student's t-test. confirmed restriction of hand2 to posterior fin rays, and also verified region-specific expression for eight other transcription factor genes: alx4a, lhx9, id4, pax9, tbx2a, hoxc8a, hoxd11a and hoxd13a. Six of these eight transcription factors have roles in AP patterning during limb or fin development (Qu et al, 1997;Harrelson et al, 2004;Zákány et al, 2004;McGlinn et al, 2005;Tzchori et al, 2009), whereas id4 has been implicated in bone homeostasis (Tokuzawa et al, 2010). The anterior expression of the Hoxc genes has been described during pectoral fin development (Molven et al, 1990), and HOXC8 has specifically been shown to be expressed in the anterior region of developing chick wings (Nelson et al, 1996).…”

The stage-dependent roles of Ldb1 and functional redundancy with Ldb2 in mammalian retinogenesis

“…2001). The conditional mutation of Ldb1 was induced on a background of Ldb2 deficiency to preclude any possible compensation for Ldb1 loss by Ldb2 (Tzchori et al, 2009;Narkis et al, 2012). Ldb1 loxP/loxP ;Ldb2 −/− embryos exhibited a normal retinal phenotype, and thus were used as controls (Fig.…”

“…Genetic and molecular studies conducted on Ldb1 and Ldb2 have revealed functional redundancy between the two factors (Tzchori et al, 2009;Narkis et al, 2012). To determine directly the potential for Ldb2 to compensate for Ldb1 deficiency during retinal development, we analyzed the retinal phenotype of embryos deficient in Ldb1 in which Ldb2 remained intact (Ldb1 loxP/loxP ; α-Cre).…”