Transgenic rescue of neurogenic atrophy in the nmd mouse reveals a role for Ighmbp2 in dilated cardiomyopathy

Abstract

Immunoglobulin mu binding protein 2 (IGHMBP2) is a DNA/RNA helicase with a putative role in transcriptional regulation and splicing. A recessive mutation of the Ighmbp2 gene in neuromuscular degeneration (nmd) mice causes progressive neurogenic atrophy of limb muscles. Affected mice show significant loss of motor neurons with large caliber axons and a moderate reduction of neurons with small caliber axons in the ventral nerve roots of the spinal cord. To investigate the role of Ighmbp2 in the pathogenesis of neuromuscular degeneration, we generated two independent lines of transgenic mice expressing the full-length Ighmbp2 cDNA specifically in neurons. Histopathological evaluation of L4 ventral nerve roots revealed that transgenic expression of the Ighmbp2 cDNA prevented primary motor neuron degeneration, while restoring the normal axonal morphology and density in nmd mice. A similar neuronal improvement is found in mutant mice carrying the CAST/EiJ-derived modifier of nmd (Mnm(C)). Intriguingly, both the transgenic and modified nmd mice went on to develop a previously unobserved cardiac and skeletal myopathy. Necropsy of nmd mice in end-stage heart failure revealed a primary dilated cardiomyopathy with secondary respiratory failure that was confirmed by in vivo ECG and echocardiographic measures. Our results suggest that reduced levels of IGHMBP2 in nmd mice compromise the integrity and function not only of motor neurons but also of skeletal and cardiac myocytes. These findings highlight the important role of IGHMBP2 in the maintenance and survival of these terminally differentiated cell types.

Motoneuron Transplantation Rescues the Phenotype of SMARD1 (Spinal Muscular Atrophy with Respiratory Distress Type 1)

“…SMARD1 is caused by a genetic defect; specifically, it results from mutations in the IGHMBP2 gene. There is no effective treatment for SMARD1 or for many other motor neuron diseases; however, recent preliminary experimental evidence has suggested that stem cell transplantation may be useful in developing therapies to treat these diseases (Harper et al, 2004;Maddatu et al, 2004;Corti et al, 2005Corti et al, , 2007Corti et al, , 2008; Deshpande et al, 2006;Yan et al, 2007). The current experiments showed that stem cell-derived motoneurons engraft efficiently in the nmd mouse spinal cord: the axons elongate toward their muscle target, and the SMARD1 phenotype is diminished.…”

“…Both male and female nmd transplanted mice had significantly increased mean life spans compared with gender-and siblingmatched nmd mice (supplemental Table 1, available at www.jneurosci.org as supplemental material). Gender differences in the life spans of nmd mice and other motor neuron disease animal models have been described previously (Maddatu et al, 2004;Corti et al, 2007). In our study, the maximum life span was 124 d in treated males and 142 in treated females (group 3); these life spans were longer than those of untreated nmd mice (i.e., groups 2 and 4; group 2, 78 d for treated males and 91 d for untreated females; group 4, 80 d for treated males and 100 d for untreated females).…”

Dysferlin Deficiency and the Development of Cardiomyopathy in a Mouse Model of Limb-Girdle Muscular Dystrophy 2B

“…All of the standard P, QRS, and T wave intervals and amplitudes were measured and the signal was averaged as described. 15 Following the conscious electrocardiograms, echocardiography was performed on the same groups of A/J and A/HeJ mice at these ages from 3 to 18 months. The Vevo 770 High-Frequency Ultrasound (Visualsonics; Toronto, Ontario, Canada) was used to obtain real-time images of cardiac function.…”

“…Hair was removed from the ventral thorax with a depilatory cream, just before standard imaging, measurements, and calculations were performed as described. 15 …”

Role of neurofilament aggregation in motor neuron disease

“…The latter models are exemplified by mutations of SMN1 in spinal muscular atrophy 81 and IGHMBP2 in spinal muscular atrophy with respiratory distress (SMARD1) 82 and nmd mice. 83,84 Altered transcriptional activity is believed to cause motor neuron disease in spinal bulbar muscular atrophy 85 and, possibly, in CMT2A disease due to recessive mutations of lamin A/C. 86 Like motor neuron degeneration associated with abnormal aggregation of mutant protein, mutations that alter gene expression occur in widely expressed proteins, raising questions as to the mechanisms accounting for the selective targeting of motor neurons.…”