Loss of Hoxa5 gene function in mice perturbs intestinal maturation

Abstract

The Hox gene family of transcription factors constitutes candidate regulators in the molecular cascade of events that governs establishment of normal terminal differentiation along the duodenum to colon axis. One member of this family, Hoxa5, displays a dynamic pattern of expression during gut development. Hoxa5 transcripts are present in midgut mesenchyme at the time of remodeling, supporting a role for this gene in digestive tract specification. To study the role of Hoxa5 in proper intestinal development and maturation, we examined whether Hoxa5 mutant mice exhibit any defect in this process. We report here that even though Hoxa5 is not required for midgut morphogenesis, its loss of function perturbs the acquisition of adult mode of digestion, which normally is temporally coordinated with the process of spontaneous weaning. Impaired maturation of the digestive tract might be related to altered specification of intestinal epithelial cells. Our findings provide evidence that Hoxa5 expression in the gut mesoderm is important for the region-specific differentiation of the adjacent endoderm.

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

“…The involvement of Hoxa5 in postnatal processes is also exemplified by its requirement for proper gut maturation and mammary gland development. 50,51 The panoply of postnatal phenotypes displayed by Hox mutants indicates that aside from the crucial role of Hox genes in embryo patterning, they fulfill a variety of functions in adult life. 19 Our study indicates that the postnatal lung defects of Hoxa5 Ϫ/Ϫ mutants have an embryonic origin, pointing to altered cell specification and behavior of goblet cells and alveolar myofibroblast progenitors.…”

Identification of Notch target genes in uncommitted T-cell progenitors: no direct induction of a T-cell specific gene program

“…Mice deficient for HoxA9 have previously been shown to display defects in myeloid, B-cell and T-cell development, 50,51 while on the other hand overexpression of HoxA10 inhibited lymphoid development. 52 HoxA5 mutant mice were generated some years ago, 53 but their hematopoietic system has not been studied. We now analyzed the BM, spleen and thymus of HoxA5 homozygous, heterozygous and wild-type littermates of 2.5, 4 and 25 weeks old.…”

Identification of Transcriptional Targets of HOXA5

“…In homozygous newborn mutants, improper tracheal and lung morphogenesis lead to tracheal occlusion and to respiratory distress associated with a marked decrease in the production of surfactant protein (10). Loss of Hoxa5 also perturbed intestinal maturation and transiently affects thyroid development (11,12). Analysis of the skeletal structures in the homozygote revealed consistent abnormalities affecting the region between sixth cervical vertebra (C6) and the first lumbar vertebra.…”