Megakaryocyte TGFß1 partitions erythropoiesis into immature progenitor/stem cells and maturing precursors.

Erythropoietin (EPO) provides the major survival signal to maturing erythroid precursors (EPs) and is essential for terminal erythropoiesis. Nonetheless, progenitor cells can irreversibly commit to an erythroid fate well before EPO acts, risking inefficiency if these progenitors are unneeded to maintain red blood cell (RBC) counts. We identified a new modular organization of erythropoiesis and, for the first time, demonstrate that the pre-EPO module is coupled to late EPO-dependent erythropoiesis by megakaryocyte (Mk) signals. Disrupting megakaryocytic transforming growth factor ß1 (Tgfb1) disorganized hematopoiesis by expanding the pre-EPO pool of progenitor cells and consequently triggering significant apoptosis of EPO-dependent EPs. Similarly, pharmacologic blockade of TGFß signaling in normal mice boosted the pre-EPO module, leading to apoptosis of EPO-sensitive EPs. Subsequent treatment with low-dose EPO triggered robust RBC production in both models. This work reveals modular regulation of erythropoiesis and offers a new strategy for overcoming chronic anemias.

The effects of repeated forced ethanol consumption during adolescence on reproductive behaviors in male rats.

Adolescence is a sensitive period of brain development when changes in hormone levels may have long-lasting effects on synaptic connections and behavior. In humans, alcohol consumption frequently begins during this critical period, although the impact of early exposure has not been fully examined. The current study was designed to investigate short- and long-term effects of repeated forced ethanol consumption during adolescence on emerging reproductive behaviors. Twenty-six young male Long-Evans rats were assigned to ethanol (Young EtOH, n = 12) or water (Young Control, n = 14) groups at postnatal day (P) 32, receiving a modified binge protocol of 3 g/kg of solution via gavage twice per week from P32 to P80. For comparison, another cohort of rats received a similar treatment paradigm in adulthood from P75-P133 (Adult EtOH, n = 8; Adult Control, n = 10). Reproductive behavior was assessed with tests for copulation, partner preference, and 50-kHz vocalizations during forced consumption (intoxication) and again after a 4-5 week period of abstinence. During forced consumption, the Young EtOH group showed significantly longer latencies on copulation tests than Young Controls, but these differences did not persist after abstinence. Different patterns were observed in Adult animals, who only showed significant, delayed impairments in the post-ejaculatory interval. Preference for sexually receptive females increased with sexual experience in both adolescent and adult rats, regardless of treatment during the forced consumption phase. However, after abstinence, the Young EtOH group showed a significantly reduced partner preference compared to the Young Control group, which may indicate long-term effects on sexual motivation. Additionally, during forced consumption the Young EtOH group tended to emit fewer ultrasonic vocalizations, perhaps reflecting impairments in sexual communication. Adult groups showed no differences in partner preference or vocalization tests at any time. Taken together, these findings indicate that repeated, intermittent ethanol exposure may have moderate effects on reproductive behavior that vary as a function of age. After abstinence, differences were only observed in the younger group, suggesting that the adolescent brain and behavior are more sensitive to ethanol exposure than the adult brain for sexual motivation and performance.