Deletion of Snai2 and Snai3 Results in Impaired Physical Development Compounded by Lymphocyte Deficiency

Abstract

The Snail family of transcriptional regulators consists of three highly conserved members. These proteins regulate (repress) transcription via the recruitment of histone deacetylases to target gene promoters that possess the appropriate E-box binding sequences. Murine Snai1 is required for mouse development while Snai2 deficient animals survive with some anomalies. Less is known about the third member of the family, Snai3. To investigate the function of Snai3, we generated a conditional knockin mouse. Utilizing Cre-mediated deletion to facilitate the ablation of Snai3 in T cells or the entire animal, we found little to no effect of the loss of Snai3 in the entire animal or in T cell lineages. This finding provided the hypothesis that absence of Snai3 was mitigated, in part, by the presence of Snai2. To test this hypothesis we created Snai2/Snai3 double deficient mice. The developmental consequences of lacking both of these proteins was manifested in stunted growth, a paucity of offspring including a dramatic deficiency of female mice, and impaired immune cell development within the lymphoid lineages.

Candidate Gene Analyses of Skeletal Variation in Malocclusion

“…Interestingly, Snai3-null mice do not show significant anomalies, suggesting that Snail genes complement each other in their biological functions (Pioli et al 2013). Snai2 and Snai3 double-knockout mice present anomalies beyond the Snai2 -/-null, including eye deformities and stunted growth (Pioli et al 2013;Fig. 5).…”

The Snail Family in Normal and Malignant Haematopoiesis

“…At the expression level, at least, there is evidence that these proteins are expressed in haematopoietic cells. Snai2 is expressed in all subsets of haematopoietic stem and progenitor cells (HSPCs), but not in more differentiated blood cells [Inoue et al, 2002;Pioli et al, 2013]. Snai1 has been detected at a low level in mature T, B, and myeloid lineage cells, while Snai3 has been detected primarily in T and B cells [Bradley et al, 2013;Pioli et al, 2013].…”

“…In contrast to Snai1-and Snai2-KO mice, loss of Snai3 had no effect on normal embryonic and adult mouse development [Bradley et al, 2013;Pioli et al, 2013]. Given their strong homology and conservation throughout evolution, it is likely that the different Snail family members can compensate for each other's loss of function.…”

“…Given their strong homology and conservation throughout evolution, it is likely that the different Snail family members can compensate for each other's loss of function. Clear functional redundancy has been observed for Snai1 and Snai2 during chondrocyte and craniofacial development [Murray et al, 2007;Chen and Gridley, 2013a, b], as well as for Snai2 and Snai3 in lymphoid development [Pioli et al, 2013[Pioli et al, , 2015. Limb bud-specific deletion of Snai1 (using Prx1-Cre) on a Snai2-null background resulted in severe defects in long-bone formation [Chen and Gridley, 2013b], while neural crest-specific deletion of Snai1 (using Wnt-Cre) on a Snai2-null background induced multiple craniofacial abnormalities, including cleft palate [Murray and Gridley, 2006].…”

“…Limb bud-specific deletion of Snai1 (using Prx1-Cre) on a Snai2-null background resulted in severe defects in long-bone formation [Chen and Gridley, 2013b], while neural crest-specific deletion of Snai1 (using Wnt-Cre) on a Snai2-null background induced multiple craniofacial abnormalities, including cleft palate [Murray and Gridley, 2006]. Similarly, double KO (DKO) of Snai2 and Snai3 resulted in male offspring skewing, B-and T-lymphoid developmental abnormalities, and severe autoimmunity [Pioli et al, 2013].…”