HoxD cluster scanning deletions identify multiple defects leading to paralysis in the mouse mutant Ironside

Abstract

A spontaneous semidominant mutation (Ironside, Irn) was isolated in mice, leading to severe hindlimb paralysis following multiple deletions in cis at the HoxD locus. To understand its cellular and molecular etiology, we embarked on a comparative analysis using systematic HoxD cluster deletions, produced via targeted meiotic recombination (TAMERE). Different lines of mice were classified according to the severity of their paralyses, and subsequent analyses revealed that multiple causative factors were involved, alone or in combination, in the occurrence of this pathology. Among them are the loss of Hoxd10 function, the sum of remaining Hoxd gene activity, and the ectopic gain of function of the neighboring gene Evx2, all contributing to the mispositioning, the absence, or misidentification of specific lumbo-sacral pools of motoneurons, nerve root homeosis, and hindlimb innervation defects. These results highlight the importance of a systematic approach when studying such clustered gene families, and give insights into the function and regulation of Hox and Evx2 genes during early spinal cord development.[Keywords: Homeosis; peroneal nerve; chromosome engineering; motoneuron] Supplemental material is available at http://www.genesdev.org.

A Flexible Bayesian Model for Testing for Transmission Ratio Distortion

“…Variability near or within the histone genes might lead to the alteration of epigenetic marks or histone expression levels, thus compromising embryo survival. Another relevant category was constituted by genes that encode transcription factors that are deeply involved in embryogenesis such as PAX5 that is essential for the genesis of the midbrain and cerebellum (Pfeffer et al 2000), HOXD genes (HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD12, and HOXD13) that are important for the innervation of the hindlimbs (Tarchini et al 2005) and digit development (Delpretti et al 2012), and DMRT1 and DMRT2 that are involved in somitogenesis (DMRT2) and sexual determination (Bellefroid et al 2013). Notably, the loss of function of DMRT1 has been recently reported as a potential cause for human spermatogenic failure (Lopes et al 2013).…”

The rise and fall of Hox gene clusters

“…Alternatively, in those animals where the elaboration of more-caudal segments is delayed in time, a mere delay in 'posterior' Hox gene activation might be sufficient to restrict their expression posteriorly, thus preventing their deleterious effects (the 'Hox clock') (Duboule, 1994b). The importance of posterior prevalence has been verified in many instances; for example, in the proper determination of pools of motoneurons (Tarchini et al, 2005) and in the early sequential migration of epiblast cells during chick gastrulation (Iimura and Pourquié, 2006).…”

Hox gene function in vertebrate gut morphogenesis: the case of the caecum

“…In order to obtain the various genotypes shown in Table 1, mice heterozygous for the HoxD allele (Zakany et al, 2004) [referred to as 'Del(1-10)'] were crossed with either del(1-13) (Zakany et al, 2001), del(4-13) (Zakany and Duboule, 1999), del(8i-13) (Tarchini et al, 2005) or del (11)(12)(13) . To produce the novel Del(4-11) allele, we used targeted meiotic recombination (TAMERE) (Hérault et al, 1998) after a cross between the del(4-13) allele and the md11f allele (Beckers and Duboule, 1998).…”