Isl1 and Ldb Co‐regulators of transcription are essential early determinants of mouse limb development

Abstract

The developing limb has served as an excellent model for studying pattern formation and signal transduction in mammalians. Many of the crucial genes that regulate growth and patterning of the limb following limb bud formation are now well known. However, details regarding the control of limb initiation and early stages of outgrowth remain to be defined. This report is focused on genetic events that pave the way for the establishment of a hindlimb bud. Fgf10 and Tbx are crucial for early phases of limb bud initiation. Here we show that in the absence of Isl1 or of Ldb1/2 there is no hindlimb bud development. Fgf10 expression in the bud mesenchyme is dependent on Isl1 and its Ldb co-regulators. Thus, Isl1 and the Ldb co-regulators of transcription are essential early determinants of mouse limb development. Isl1/Ldb complexes regulate Fgf10 to orchestrate the earliest stages of hindlimb formation.

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

“…We characterized Ldb1 expression in the developing and differentiated retina as it is considered to play fundamental roles and to compensate for Ldb2 loss in various developmental processes (Mukhopadhyay et al, 2003;Narkis et al, 2012). Indeed, Ldb1 seemed to be sufficient to support retinal development, as we did not detect any alterations in OC morphology, differentiation to retinal cell types and lamination in the Ldb1 loxP/loxP ;Ldb2 −/− embryos ( Fig.…”

“…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.…”

“…Ldb1 plays key roles during development and can compensate for most of the activities of Ldb2 (Mukhopadhyay et al, 2003;Narkis et al, 2012;Leone et al, 2016). Ldb2-null mice are fertile and phenotypically normal, whereas Ldb1-null embryos die at early stages of neurogenesis (E9.5-10.0), owing to multiple developmental aberrations, including the truncation of head structures (Mukhopadhyay et al, 2003).…”

“…Ldb1 has been shown to fulfill several important functions: it has an essential role in the development of the CNS and is crucial for specification and maintenance of hematopoietic stem cells (Li et al, 2011). Moreover, Ldb1, together with Isl1, is a key early regulator of mammalian limb and cardiac development (Narkis et al, 2012;Caputo et al, 2015).…”

Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood

“…2C). Interestingly, we observed that LDB1, a LIM-only containing protein often found to be a necessary cofactor of ISL1 in different regulatory contexts (23,24), also binds in vivo to nPE1 and nPE2, but not to the region between them (Fig. 2C).…”