PubMed · 10235254
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J Lippincott-Schwartz. 1999-04-29. Coated-pit dynamics.. https://doi.org/10.1038/19632
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Microdeletion of chromosome 22q11.2 is commonly associated with congenital cardiovascular defects that involve development of cranial neural crest cells (NCC) that emigrate through the pharyngeal arches. UFD1l is one of several candidate genes for 22q11.2 deletion syndrome (22q11DS). UFD1l encodes a protein whose yeast counterpart is involved in a ubiquitin-dependent proteolytic degradation pathway; however, the role of UFD1L in NCC development remains unknown. Mouse embryos that lack Ufd1l die before organogenesis. We have therefore studied the function of Ufd1l in the chick system. Chick Ufd1l encoded a 307-amino acid protein that was highly conserved with mouse and human UFD1L. Chick Ufd1l was expressed in the developing neural tube, NCC, and mesenchyme of the head and pharyngeal arch structures, as well as in the conotruncal region (cardiac outflow tract), consistent with the clinical features of 22q11DS. To determine loss-of-function effects of chick Ufd1l in NCC, we infected cardiac NCC with a retrovirus expressing antisense Ufd1l transcripts in chick embryos before their migration. Morphologic analysis of infected embryos at a later developmental stage demonstrated that functional attenuation of chick Ufd1l in cardiac NCC resulted in an increased incidence of conotruncal septation defects. These data suggest that Ufd1l may play a role in cardiac NCC during conotruncal septation.
Recent research indicates that the novel multimodular adaptor protein EHSH1 plays an important role in a partnership between clathrin-mediated endocytosis and intracellular signaling pathways, including the MAPK pathway, receptor-tyrosine kinase/ras-mediated pathway, and the rho family of the GTPase-dependent pathway. We report the detailed expression pattern of EHSH1 in the rat CNS, using separate cultures of neurons, astrocytes, and microglia, and biochemical and immunohistochemical analyses. Cultured neurons from the cortex express primarily the long isoform EHSH1-l, as well as a small amount of the short isoform EHSH1-s. Cultured astrocytes express EHSH1-s, at a level similar to neurons, and a trace of EHSH1-l. Cultured microglia express only EHSH1-s. Double immunofluorescent staining of cortical sections showed that EHSH1 is expressed predominantly in neurons. These results suggest that EHSH1-l is a primary isoform and that EHSH1-l is highly enriched in neurons in the rat adult CNS. Immunohistochemistry of a series of brain sections revealed widespread distribution of EHSH1 throughout the brain. Particularly intense immunoreactivity was observed in the somatodendritic region of neurons in Layer III of the neocortex, hippocampus, globus pallidus, subthalamic nucleus, and substantia nigra. Interestingly, all pyramidal neurons in Layer III of the neocortex and hippocampus did not necessarily exhibit equal levels of immunostaining. In contrast, little EHSH1 immunoreactivity was detected in septofimbrial nucleus and subfornical organ of the septal region, and solitary tract and external cuneate nuclei of the medulla. Variety in the expression of EHSH1 in neurons of different regions may reflect different conditions in clathrin-mediated endocytosis and the following signal transduction.
The Src family of nonreceptor tyrosine kinases plays an important role in modulating signals that affect growth cone extension, neuronal differentiation, and brain development. Recent reports indicate that the Src SH2/SH3 binding partner AFAP-110 has the capacity to modulate actin filament integrity as a cSrc activating protein and as an actin filament bundling protein. Both AFAP-110 and a brain specific isoform called AFAP-120 (collectively referred to as AFAP) exist at high levels in chick embryo brain. We sought to identify the localization of AFAP in mouse brain in order to identify its expression pattern and potential role as a cellular modulator of Src family kinase activity and actin filament integrity in the brain. In E16 mouse embryos, AFAP expression levels were very high and concentrated in the olfactory bulb, cortex, forebrain, cerebellum, and various peripheral sensory structures. In P3 mouse pups, overall expression was reduced compared to E16 embryos, and AFAP was found primarily in olfactory bulb, cortex, and cerebellum. AFAP expression levels were significantly reduced in adult mice, with high expression levels only detected in the olfactory bulb. Western blot analysis indicated that concentrated expression of AFAP correlates well with the AFAP-120 isoform, which appears to be a splice variant of AFAP-110. As the expression pattern of AFAP overlaps with the reported expression patterns of cSrc and Fyn, we hypothesize that AFAP is positioned to modulate signal transduction cascades that direct activation of these nonreceptor tyrosine kinases and concomitant cellular changes that occur in actin filaments during brain development.