During pituitary organogenesis, the progressive differentiation of distinct pituitary-specific cell lineages from a common primordium involves a series of developmental decisions and inductive interactions. Targeted gene disruption in mice showed that Lhx3, a LIM homeobox gene expressed in the pituitary throughout development, is essential for differentiation and proliferation of pituitary cell lineages. In mice homozygous for the Lhx3 mutation, Rathke's pouch formed but failed to grow and differentiate; such mice lacked both the anterior and intermediate lobes of the pituitary. The determination of all pituitary cell lineages, except the corticotrophs, was affected, suggesting that a distinct, Lhx3-independent ontogenetic pathway exists for the initial specification of this lineage.
Of the five known dopamine receptors, DlA and D2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei ofthe basal ganglia. Movement The pivotal role played by dopamine receptors in the pathophysiology and treatment ofParkinson disease (1) and schizophrenia (2) and in the mode of action of addictive drugs such as amphetamine and cocaine (3, 4) is well established. Of the five known dopamine receptor subtypes (5), the DlA and D2 receptors account for the vast majority of dopamine receptors (6) expressed in the striatum. The DlA (also known as D, in the primate system) and D2 receptor subtypes are expressed mainly by spiny projection neurons, which account for 90-95% of the striatal neuron population (7). These striatal neurons may be subdivided into two major types on the basis of their axonal projections. One type provides a direct projection to the output nuclei of the basal ganglia: the substantia nigra and entopeduncular nucleus (the internal segment of the globus pallidus in primates). The other type provides projections to the globus pallidus (the external segment of the primate globus pallidus). As this latter type is connected indirectly to the output nuclei of the basal ganglia through connections with the subthalamic nucleus, the two output pathways are referred to as the direct and indirect output systems. Striatal neurons giving rise to the direct pathway express high levels of the DlA dopamine receptor subtype and the neuropeptides substance P and dynorphin, whereas neurons giving rise to the indirect pathway express high levels of the D2 dopamine receptor and the peptide enkephalin (7). The levels of peptide expression in these neurons provide an assay oftheir activity (7), as neuropeptide levels correlated with fuing rates in target neurons (1).Current models suggest that imbalanced activity in the direct and indirect pathways is responsible for clinical movement disorders (8). A number of studies have demonstrated that dopamine oppositely effects these two output pathways through their differential expression ofthe DlA and D2 receptors (7). For example, depletion of striatal dopamine with lesions of the nigrostriatal dopamine pathway in animal models of Parkinson disease results in reduced expression of substance P in direct output neurons and increased enkephalin expression in indirect striatal output neurons. Moreover, these changes may be selectively reversed with selective dopamine receptor agonist treatments, so that D1 agonist treatment normalizes substance P levels whereas D2 agonist treatment normalizes enkephalin levels (9). While these studies have demonstrated the differential role of DlA and D2 receptors in striatal function, important questions concerning the interaction between these neuronal pathways remain. To provide an experimental animal model to address the...
During mammalian embryonic development, the ovaries and testes develop from somatic cells of the urogenital ridges as indifferent gonads, harbouring primordial germ cells that have migrated there. After sex determination of the gonads, the testes produce testosterone and anti-Mullerian hormone which mediate male sexual differentiation, and the female developmental pathway ensues in their absence. Here we show that transcripts of the LIM homeobox gene Lhx9 are present in urogenital ridges of mice at embryonic day 9.5; later they localize to the interstitial region as morphological differentiation occurs. In mice lacking Lhx9 function, germ cells migrate normally, but somatic cells of the genital ridge fail to proliferate and a discrete gonad fails to form. In the absence of testosterone and anti-Mullerian hormone, genetically male mice are phenotypically female. The expression of steroidogenic factor 1 (Sf1), a nuclear receptor essential for gonadogenesis, is reduced to minimal levels in the Lhx9-deficient genital ridge, indicating that Lhx9 may lie upstream of Sf1 in a developmental cascade. Unlike mice lacking other genes that mediate early stages of gonadogenesis, Lhx9 mutants do not exhibit additional major developmental defects. Thus, LHX9 mutations may underlie certain forms of isolated gonadal agenesis in humans.
Gaucher's disease is the most prevalent lysosomal storage disorder in humans and results from an autosomally inherited deficiency of the enzyme glucocerebrosidase (beta-D-glucosyl-N-acylsphingosine glucohydrolase), which is responsible for degrading the sphingolipid glucocerebroside. An animal model for Gaucher's disease would be important for investigating its phenotypic diversity and pathogenesis and for evaluating therapeutic approaches. A naturally occurring canine model has been reported but not propagated. Attempts to mimic the disease in animals by inhibiting glucocerebrosidase have been inadequate. Here we generate an animal model for Gaucher's disease by creating a null allele in embryonic stem cells through gene targeting and using these genetically modified cells to establish a mouse strain carrying the mutation. Mice homozygous for this mutation have less than 4% of normal glucocerebrosidase activity, die within twenty-four hours of birth and store glucocerebroside in lysosomes of cells of the reticuloendothelial system.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.