The role of the glucocorticoid receptor {GR1 in glucocorticoid physiology and during development was investigated by generation of GR-deficient mice by gene targeting. GR -/-mice die within a few hours after birth because of respiratory failure. The lungs at birth are severely atelectatic, and development is impaired from day 15.5 p.c. Newborn livers have a reduced capacity to activate genes for key gluconeogenic enzymes. Feedback regulation via the hypothalamic-pituitary-adrenal axis is severely impaired resulting in elevated levels of plasma adrenocorticotrophic hormone (15-fold) and plasma corticosterone (2.5-fold). Accordingly, adrenal glands are enlarged because of hypertrophy of the cortex, resulting in increased expression of key cortical steroid biosynthetic enzymes, such as side-chain cleavage enzyme, steroid 11B-hydroxylase, and aldosterone synthase. Adrenal glands lack a central medulla and synthesize no adrenaline. They contain no adrenergic chromaffin cells and only scattered noradrenergic chromaffin cells even when analyzed from the earliest stages of medulla development. These results suggest that the adrenal medulla may be formed from two different cell populations: adrenergic-specific cells that require glucocorticoids for proliferation and/or survival, and a smaller noradrenergic population that differentiates normally in the absence of glucocorticoid signaling.

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine, whose numerous cell and tissue activities include cell-cycle control, the regulation of early development, differentiation, extracellular matrix formation, hematopoesis, angiogenesis, chemotaxis, immune functions, and the induction of apoptosis. TGF-beta-mediated growth inhibition and apoptosis can be correlated with its function as a tumor suppressor. The apoptosis-inducing capacity has been investigated in many cell types. Data from cell-culture experiments and in vivo studies argue for a pivotal role of TGF-beta-mediated apoptosis in the maintenance of B- and T-cell homeostasis. The importance of TGF-beta in the control of liver cell apoptosis and cell death of prostate epithelial cells has been confirmed in many studies. Inactivation of TGF-beta in animal models via a knockout approach or neutralizing antibodies suggests that TGF-beta-mediated apoptosis plays an important part during tissue formation and remodeling and during the phase of ontogenetic neuron death. The molecular mechanisms involved in these processes seem to involve the activation of SMAD proteins. Many studies have described an interaction of TGF-beta with other signaling cascades as exemplified by the requirement of AP1 transcription factor for the induction of apoptosis in liver cells. The aim of this review is (1) to summarize and classify data in the TGF-beta apoptosis literature with respect to the affected cell types, (2) to provide insights into the intracellular mechanisms involved in TGF-beta-mediated apoptosis, and (3) to set TGF-beta-mediated apoptosis in a physiological context.

The hemispheric, bi-layered optic cup forms from an oval optic vesicle during early vertebrate eye development through major morphological transformations. The overall basal surface, facing the developing lens, is increasing, while, at the same time, the space basally occupied by individual cells is decreasing. This cannot be explained by the classical view of eye development. Using zebrafish (Danio rerio) as a model, we show that the lens-averted epithelium functions as a reservoir that contributes to the growing neuroretina through epithelial flow around the distal rims of the optic cup. We propose that this flow couples morphogenesis and retinal determination. Our 4D data indicate that future stem cells flow from their origin in the lens-averted domain of the optic vesicle to their destination in the ciliary marginal zone. BMP-mediated inhibition of the flow results in ectopic neuroretina in the RPE domain. Ultimately the ventral fissure fails to close resulting in coloboma.DOI: http://dx.doi.org/10.7554/eLife.05216.001

The superfamily of transforming growth factors‐beta (TGF‐beta) comprises an expanding list of multifunctional proteins serving as regulators of cell proliferation and differentiation. Prominent members of this family include the TGF‐beta s 1‐5, activins, bone morphogenetic proteins and a recently discovered glial cell line‐derived neurotrophic factor (GDNF). In the present study we demonstrate and compare the survival promoting and neuroprotective effects of TGF‐beta 1, ‐2 and ‐3, activin A and GDNF for midbrain dopaminergic neurons in vitro. All proteins increase the survival of tyrosine hydroxylase‐immunoreactive dopaminergic neurons isolated from the embryonic day (E) 14 rat mesencephalon floor to varying extents (TGF‐beta s 2.5‐fold, activin A and GDNF 1.6‐fold). TGF‐beta s, activin A and GDNF did not augment numbers of very rarely observed astroglial cells visualized by using antibodies to glial fibrillary acidic protein and had no effect on cell proliferation monitored by incorporation of BrdU. TGF‐beta 1 and activin A protected dopaminergic neurons against N‐methyl‐4‐phenylpiridinium ion toxicity. Reverse transcription‐polymerase chain reaction (RT‐PCR) analysis indicated that TGF‐beta 2 mRNA, but not GDNF mRNA, is expressed in the E14 rat midbrain floor and in mesencephalic cultures. We conclude that TGF‐beta s 1‐3, activin A and GDNF share a neurotrophic capacity for developing dopaminergic neurons, which is not mediated by astroglial cells and not accompanied by an increase in cell proliferation.

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