The thymus and parathyroid glands in mice develop from a thymus/parathyroid primordium that forms from the endoderm of the third pharyngeal pouch. We investigated the molecular mechanisms that promote this unique process in which two distinct organs form from a single primordium, using mice mutant for Hoxa3 and Pax1. Thymic ectopia in Hoxa3(+/-)Pax1(-/-) compound mutants is due to delayed separation of the thymus/parathyroid primordium from the pharynx. The primordium is hypoplastic at its formation, and has increased levels of apoptosis. The developing third pouch in Hoxa3(+/-)Pax1(-/-) compound mutants initiates normal expression of the parathyroid-specific Gcm2 and thymus-specific Foxn1 genes. However, Gcm2 expression is reduced at E11.5 in Pax1(-/-) single mutants, and further reduced or absent in Hoxa3(+/-)Pax1(-/-) compound mutants. Subsequent to organ-specific differentiation from the shared primordium, both the parathyroids and thymus developed defects. Parathyroids in compound mutants were smaller at their formation, and absent at later stages. Parathyroids were also reduced in Pax1(-/-) mutants, revealing a new function for Pax1 in parathyroid organogenesis. Thymic hypoplasia at later fetal stages in compound mutants was associated with increased death and decreased proliferation of thymic epithelial cells. Our results suggest that a Hoxa3-Pax1 genetic pathway is required for both epithelial cell growth and differentiation throughout thymus and parathyroid organogenesis.
A novel agrin isoform was identified based on the isolation of an agrin cDNA from E9 chick brain that lacked 21 base pairs (bp) in the NH2-terminal encoding region of the agrin mRNA. Reverse transcription-polymerase chain reaction (RT-PCR) of E9 chick brain mRNA confirmed the existence of this agrin isoform in brain, although the novel splice variant represents a minor fraction of agrin mRNA in brain. However, upon analysis of chick brain astrocyte mRNA, smooth muscle mRNA, and cardiac muscle mRNA by RT-PCR, we show that this novel agrin isoform is the predominant agrin isoform in these non-neuronal cell populations. We extended our analyses to examine the expression of this agrin mRNA isoform during chick development and show that the agrin mRNA lacking this 21-bp exon is up-regulated with brain development, consistent with the increase in glial number during brain development, while the agrin isoform that does not undergo splicing and thus contains the 21-bp exon is down-regulated in brain development. Because the 21-bp exon is inserted in the region of chick agrin which encodes the putative signal sequence of agrin, with the signal peptidase site immediately preceding the putative first amino acid of the mature protein being deleted as a result of splicing, these data raise the interesting possibility that the presence or absence of this alternatively spliced exon may differentially regulate processing of the agrin protein in neuronal and non-neuronal cells, respectively.
SUMMARY
The vomeronasal organ (VNO) has evolved to link an animal's behavior to its environment in a highly species-specific fashion. In mice, it is thought to be the primary sensory system responsible for the detection of pheromones. Pheromones regulate a variety of responses including mate recognition in the context of selective pregnancy failure. MHC (major histocompatibility complex)class I peptides have been identified as compounds that elicit the pregnancy block effect via the VNO. However, the transduction cascade of these molecules is unknown and it is not known if the production of these compounds are androgen dependent. By using male urine and MHC peptides, we show that female mice treated with MHC peptides (in urine or PBS) and urine from castrated males or juvenile mice of different haplotypes respond to the Bruce Effect paradigm in a manner equivalent to female mice exposed to whole urine. In addition to providing new evidence that urine from castrated or juvenile males and MHC peptides can induce pregnancy block, we show correlation of the effect with an increase in inositol 1,4,5-trisphosphate.
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