RESUMEN
The leucine-rich acidic nuclear protein (LANP) belongs to a family of evolutionarily conserved proteins that are characterized by an amino-terminal domain rich in leucine residues followed by a carboxy-terminal acidic tail. LANP has been implicated in the regulation of a variety of cellular processes including RNA transport, transcription, apoptosis, vesicular trafficking, and intracellular signaling. Abundantly expressed in the developing cerebellum, this protein has also been hypothesized to play a role in cerebellar morphogenesis. LANP has been implicated in disease biology as well, both as a mediator of toxicity in spinocerebellar ataxia type 1 and as a tumor suppressor in cancers of the breast and prostate. To better understand the function of this multifaceted protein, we have generated mice lacking LANP. Surprisingly, these mice are viable and fertile. In addition we could not discern any derangements in any of the major organ systems, including the nervous system, which we have studied in detail. Overall our results point to a functional redundancy of LANP's function, most likely provided by its closely related family members.
Asunto(s)
Neuropéptidos/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Animales , Conducta Animal/fisiología , Encéfalo/citología , Encéfalo/metabolismo , Electrofisiología , Femenino , Viabilidad Fetal , Marcación de Gen , Humanos , Inmunohistoquímica , Técnicas In Vitro , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuropéptidos/clasificación , Neuropéptidos/genética , Proteínas Nucleares/clasificación , Proteínas Nucleares/genética , Fosfoproteínas/clasificación , Fosfoproteínas/genética , FilogeniaRESUMEN
Girls with MLS syndrome have microphthalmia with linear skin defects of face and neck, sclerocornea, corpus callosum agenesis and other brain anomalies. This X-linked dominant, male-lethal condition is associated with heterozygous deletions of a critical region in Xp22.31, from the 5' untranslated region of MID1 at the telomeric boundary to the ARHGAP6 gene at the centromeric boundary. HCCS, encoding human holocytochrome c-type synthetase, is the only gene located entirely inside the critical region. Because single gene analysis is not feasible in MLS patients (all have deletions), we generated a deletion of the equivalent region in the mouse to study the molecular basis of this syndrome. This deletion inactivates mouse Hccs, whose homologs in lower organisms (cytochrome c or c1 heme lyases) are essential for function of cytochrome c or c1 in the mitochondrial respiratory chain. Ubiquitous deletions generated in vivo lead to lethality of hemizygous, homozygous and heterozygous embryos early in development. This lethality is rescued by expression of the human HCCS gene from a transgenic BAC, resulting in viable homozygous, heterozygous and hemizygous deleted mice with no apparent phenotype. In the presence of the HCCS transgene, the deletion is easily transmitted to subsequent generations. We did obtain a single heterozygous deleted female that does not express human HCCS, which is analogous to the low prevalence of the heterozygous MLS deletion in humans. Through the study of these genetically engineered mice we demonstrate that loss of HCCS causes the male lethality of MLS syndrome.