Congenital diaphragmatic hernia, kidney agenesis and cardiac defects associated with Slit3-deficiency in mice

Abstract

Slit3 along with Slit1 and Slit2 comprise the Slit family of proteins. The latter two proteins are known to be involved in axon guidance and cell migration during animal development. However, little is know about the functions of Slit3. We created a Slit3-deficient mouse model from an OmniBank ES cell line with a Slit3 allele trapped by insertional mutagenesis to analyze the in vivo functions of this protein. In this model, congenital diaphragmatic hernia is the most obvious phenotype. Herniation was found to be caused by a defective central tendon (CT) of the diaphragm that remained fused with the liver. Electron microscopic analyses of the defective CT revealed disorganized collagen fibrils that failed to form tight collagen bundles. The hearts of Slit3-deficient mice have an enlarged right ventricle. In addition, 20% of homozygous mice also showed a range of kidney defects that include unilateral or bilateral agenesis of the kidney and ureter, or varying degrees of renal hypoplasia. Thus, we concluded that Slit3 is involved in the development of multiple organ systems that include the diaphragm and the kidney. Slit3-deficient mice represent a genetic animal model for physiological and pathological studies of congenital diaphragmatic hernia.

Repulsive axon guidance molecule Slit3 is a novel angiogenic factor

“…8,23 We extended this finding and observed that Slit3 is expressed and secreted by both ECs and VSMCs, the 2 major cell types of vasculature. We also observed that Robo1 and Robo4 are universally expressed by ECs in various organs (Figure 1).…”

“…In contrast, Slit3 is widely expressed in the central nervous system and peripheral tissues and organs, such as the developing tongue, kidney, genital ridge, pharynx, umbilical cord vein, atrial wall of heart, lung, and diaphragm. [7][8][9] Consistent with the expression patterns, the authors of mouse genetic studies [8][9][10] have established that Slit1 and Slit2 are essential for neural development, whereas Slit3 is dispensable. Instead, Slit3 is required for diaphragm and kidney genesis, revealing that Slit3 critically regulates non-neuron-related developmental processes.…”

“…5,6 Slit1-3 show both overlapping and distinct expression patterns. [7][8][9] Slit1 and Slit2 are expressed prominently in the central nervous system. In contrast, Slit3 is widely expressed in the central nervous system and peripheral tissues and organs, such as the developing tongue, kidney, genital ridge, pharynx, umbilical cord vein, atrial wall of heart, lung, and diaphragm.…”

“…Instead, Slit3 is required for diaphragm and kidney genesis, revealing that Slit3 critically regulates non-neuron-related developmental processes. 8,9 Angiogenesis refers to the generation of new blood vessels from existing capillary plexus in response to angiogenic stimuli. [11][12][13] Angiogenesis is finely orchestrated, in which growing vessels navigate through a complex extracellular environment to their target sites in a tightly controlled series of guidance decisions.…”

Moving away from the midline: new developments for Slit and Robo

“…In vertebrates, Slit/Robo function was also proposed to contribute to the development of the cardiovascular system (Calmont et al, 2009;Liu et al, 2003), although it is still unknown whether this involves a classic, repulsive, mechanism or cadherin-dependent cell adhesion.…”