No abstract

Transforming growth factor-beta are cytokines with a wide range of biological effects. They play a pathologic role in inflammatory and fibrosing diseases such as nephrosclerosis. TGF-beta s are secreted in a latent form due to noncovalent association with latency associated peptide (LAP), which is a homodimer formed from the propeptide region of TGF-beta. LAP is disulfide linked to another protein, latent TGF-beta binding protein (LTBP). LTBP has features in common with extracellular matrix proteins, and targets latent TGF-beta to the matrix. Activation of latent TGF-beta can be accomplished in vitro by denaturing treatments, plasmin digestion, ionizing radiation and interaction with thrombospondin. The mechanisms by which latent TGF-beta is activated physiologically are not well understood. Results to date suggest an important role for proteases, particularly plasmin, although other mechanisms probably exist. A general model of activation is proposed in which latent TGF-beta is released from the extracellular matrix by proteases, localized to cell surfaces, and activated by cell-associated plasmin.

Dopaminergic (DA) neurons of substantia nigra in the midbrain control voluntary movement, and their degeneration is the cause of Parkinson's disease. The complete set of genes required to specifically determine the development of midbrain DA subgroups is not known yet. We report here that mice lacking the bicoidrelated homeoprotein Pitx3 fail to develop DA neurons of the substantia nigra. Other mesencephalic DA neurons of the ventral tegmental area and retrorubral field are unaltered in their dopamine expression and histological organization. These data suggest that Pitx3-dependent gene expression is specifically required for the differentiation of DA progenitors within the mesencephalic DA system. M idbrain dopaminergic (DA) cells contribute to the control of voluntary movement, cognition, and emotional behavior. Degeneration of these cells results in Parkinson's disease, and aberrant dopamine neurotransmitter signaling is implicated in schizophrenia and addictive behavioral disorders (1-3). Within the midbrain there are three subgroups of DA neurons, the ventral tegmental area (VTA͞A10), substantia nigra (SN͞ A9), and retrorubral field (RRF͞A8), that together constitute the mesencephalic (mes) system (4). Those DA cells in the SN that innervate the striatum preferentially degenerate in Parkinson's disease, whereas other DA subgroups regulate emotional and reward behaviors.Transcription factors regulate the differentiation of midbrain DA neuron precursors. Two transcription factors have been shown to contribute to different aspects of mesDA neuronal differentiation. One of these, the orphan nuclear hormone receptor Nurr1, is required for maturation of mesDA neuron precursors. Mice harboring null alleles of Nurr1 do not express tyrosine hydroxylase (TH), which catalyzes the initial step of dopamine neurotransmitter biosynthesis (5-11). The other factor, LIM homeodomain transcription factor Lmx1b, contributes partially to the specification of mesDA neuronal progenitors beginning on embryonic day 12.5 in the mouse but is not essential for TH gene expression (12).A third transcription factor, the bicoid-related homeodomain-containing transcription factor Pitx3, which is also known as Ptx3, has been implicated in the development of DA neurons. Pitx3 gene expression is restricted to the developing eye and DA progenitor cells from embryonic day 11 throughout adult life in mice (13,14). In the brain, Pitx3 mRNA localizes specifically to the SN and VTA (14). A reduction in Pitx3 mRNA levels is observed in the ventral midbrain of Lmx1b knockout mice, 6-hydroxydopamine-lesioned rats, and Parkinson's patients (8,11,12,14). Yet, Pitx3 expression is maintained in the ventral midbrain of Nurr1 null mutant embryos (12). These data have been interpreted to suggest that Pitx3 contributes to the combinatorial code defined by multiple transcription factors that establish specification and differentiation of midbrain DA progenitors (12). Here we report that Pitx3 is essential for the development of neurons specific to the SN. The D...