Biomedical subjects

José G Pichel

Publications and source records attributed to José G Pichel.

4 recordsLinked to original sources

PubMed2006

Alterations in alveolar epithelium differentiation and vasculogenesis in lungs of LIF/IGF-I double deficient embryos.

Previous studies on double deficient mice for leukemia inhibitory factor (LIF) and insulin-like growth factor I (IGF-I) reported that they died of respiratory failure, with abnormal lung histology and altered expression of pulmonary markers. Here we analyzed prenatal Lif/Igf-I double mutant mouse embryos to characterize LIF and IGF-I cooperative roles in distal lung epithelium and vascular maturation. Lungs of IGF-I-deficient embryos displayed a higher proportion of type II pneumocytes, less differentiated type I pneumocytes, and failure in alveolar capillary remodeling compared to wild type and LIF-deficient mice. Lif/Igf-I double knockout lungs showed aggravated pulmonary hypoplasia, lower airway volume, increased proliferation, and elevated levels of ERK1/2 activation. In addition, their alveoli were collapsed and lined by type II cells. The differentiation of type I cells barely occurred and capillaries remained in the abundant mesenchyme. These results indicate that LIF collaborates with IGF-I in lung alveolar epithelium and vascular maturation.

Animals↗

PubMed2004

Mice lacking IGF-I and LIF have motoneuron deficits in brain stem nuclei.

We analyzed the neural embryonic phenotype of single and double-mutant mice for insulin-like growth factor-I (IGF-I) and leukemia inhibitory factor (LIF). The anatomical structure of the hippocampus, the cerebellum, and the olfactory epithelium, regions showing expression of both factors and their receptors, appeared largely normal in all mutant mice. In the fimbria and the spinal cord, similar patterns of glial fibrillary acidic protein (GFAP)-expressing astrocytes were found in wild-type and mutant mice. In contrast, single Igf-I and double-mutant mice showed a significant reduction in the number of trigeminal and facial motoneurons, whereas mice lacking LIF showed a significant reduction of trigeminal motoneurons. These results suggest that IGF-I and LIF regulate cooperatively motoneuron numbers in specific brain stem nuclei.

Animals↗

PubMed2002

Gdnf haploinsufficiency causes Hirschsprung-like intestinal obstruction and early-onset lethality in mice.

Hirschsprung disease (HSCR) is a common congenital disorder that results in intestinal obstruction and lethality, as a result of defective innervation of the gastrointestinal (GI) tract. Despite its congenital origin, the molecular etiology of HSCR remains elusive for >70% of patients. Although mutations in the c-RET receptor gene are frequently detected in patients with HSCR, mutations in the gene encoding its ligand (glial cell line-derived neurotrophic factor [GDNF]), are rarely found. In an effort to establish a possible link between human HSCR and mutations affecting the Gdnf locus, we studied a large population of mice heterozygous for a Gdnf null mutation. This Gdnf(+/-) mutant cohort recapitulates complex features characteristic of HSCR, including dominant inheritance, incomplete penetrance, and variable severity of symptoms. The lack of one functioning Gdnf allele causes a spectrum of defects in gastrointestinal motility and predisposes the mutant mice to HSCR-like phenotypes. As many as one in five Gdnf(+/-) mutant mice die shortly after birth. Using a transgenic marking strategy, we identified hypoganglionosis of the gastrointestinal tract as a developmental defect that renders the mutant mice susceptible to clinical symptoms of HSCR. Our findings offer a plausible way to link an array of seemingly disparate features characteristic of a complex disease to a much more narrowly defined genetic cause. These findings may have general implications for the genetic analysis of cause and effect in complex human diseases.

Age of Onset↗

PubMed2002

Cochlear abnormalities in insulin-like growth factor-1 mouse mutants.

Insulin-like growth factor 1 (IGF-1) modulates inner ear cell proliferation, differentiation and survival in culture. Its function in human hearing was first evidenced by a report of a boy with a homozygous deletion of the Igf-1 gene, who showed severe sensorineural deafness [Woods et al., New Engl. J. Med. 335 (1996) 1363-1367]. To better understand the in vivo role of IGF-1 during inner ear differentiation and maturation, we studied the cochleae of Igf-1 gene knockout mice by performing morphometric stereological analyses, immunohistochemistry and electron microscopy on postnatal days 5 (P5), P8 and P20. At P20, but not at P5, the volumes of the cochlea and cochlear ganglion were significantly reduced in mutant mice, although the reduction was less severe than whole body dwarfism. A significant decrease in the number and average size of auditory neurons was also evident at P20. IGF-1-deficient cochlear neurons showed increased apoptosis, along with altered expression of neurofilament 200 kDa and vimentin. The eighth nerve, the cochlear ganglion and the fibers innervating the sensory cells of the organ of Corti of the P20 mouse mutants presented increased expression of vimentin, whereas the expression of neurofilament was decreased. In addition, the myelin sheath was severely affected in ganglion neurons. In conclusion, IGF-1 deficit in mice severely affects postnatal survival, differentiation and maturation of the cochlear ganglion cells.

Aging↗