The LIM-homeodomain transcription factors Lmx1a and Lmx1b play critical roles during the development of midbrain dopaminergic progenitors, but their functions in the adult brain remain poorly understood. We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons. Strikingly, inactivation of Lmx1a and Lmx1b recreates cellular features observed in Parkinson's disease. We found that Lmx1a/b control the expression of key genes involved in mitochondrial functions, and their ablation results in impaired respiratory chain activity, increased oxidative stress, and mitochondrial DNA damage. Lmx1a/b deficiency caused axonal pathology characterized by α-synuclein + inclusions, followed by a progressive loss of dopaminergic neurons. These results reveal the key role of these transcription factors beyond the early developmental stages and provide mechanistic links between mitochondrial dysfunctions, α-synuclein aggregation, and the survival of dopaminergic neurons. M idbrain dopaminergic (mDA) neurons control key functions in the mammalian brain, including voluntary movement, associative learning, and motivated behaviors. Dysfunctions of the dopaminergic (DA) system underlie a wide variety of neurological and psychiatric disorders. The progressive and rather selective degeneration of mDA neurons is one of the principal pathological features of Parkinson's disease (PD) (1). In PD, neuronal loss is accompanied by the appearance of α-synucleinenriched intraneuronal inclusions called "Lewy bodies" and "Lewy neurites." The etiologies of PD remain unsolved, but mitochondrial dysfunction emerges as a central mechanism in inherited, sporadic, and toxin-induced PD (2).Specification of the subtype identities of mDA neurons begins during embryonic development. The combinatory activation of transcription factors (TFs) and their target genes allows the progenitors to mature progressively and terminally differentiate into postmitotic neuron subtypes. Tremendous efforts have been made to describe the complex spatiotemporal expression of TFs during mDA neuronal development (see refs. 3 and 4 for reviews). After mDA neuron maturation, a large number of developmentally expressed TFs remain active throughout adulthood. Our knowledge of the functional roles of these TFs in mature neurons remains rudimentary. Accumulating evidence shows that transcription factors including the nuclear receptor related 1 protein (Nurr1), En1, Pitx3, Otx2, and Foxa2, which are recognized for their role in the early development of mDA neurons, are also required for the maintenance of phenotypic neuronal identity in the adult (5).The LIM homeodomain genes Lmx1a/b are early determinants of the fate of mDA progenitors (6), and their actions are essential at each step of DA neuronal generation (7,8). The murine Lmx1a and Lmx1b proteins are closely related and share an overall amino acid identity of 64%, with 100% identity in their homeodomain and 67% and 83% identity in each LIM domain (9). These neuron...

SUMMARY1. The production of heat and (internal) work and the changes in the amount of phosphocreatine (PCr), ATP, inorganic phosphate (Pi) and sometimes lactate have been measured from moment to moment during and after tetanic isometric contractions of isolated frog muscles at 0°C.2. Heat production was measured by thermopiles and a novel apparatus was employed for freezing the muscles rapidly at a chosen instant so as to halt the chemical processes before analysis.3. Using unpoisoned muscles in oxygen, it was shown that neither oxidative recovery processes nor glycolytic ones led to appreciable restitution of PCr or ATP during 15 see of contraction. However, clear signs of recovery processes could be seen within a minute. In our preparations artificial 'ageing' by storage at low temperature did not interfere with the capacity for glycolysis.4. Our clearest result was that the break-down of PCr was not nearly large enough to account for the rapid heat production during the first few sec of contraction. By the end of a 15 see tetanus as much as 10 mcal/g remained unaccounted for.5. The source of this heat is not clear. At no time is there any sign of net

SUIMMARY1. The production of heat (h) and work (w) and the changes in phosphocreatine (PCr) and ATP have been measured on tetanized isolated frog muscles (unpoisoned and in oxygen at 00 C) during shortening at constant velocity and during isometric contraction (both without relaxation). The former type of contraction was designed to maximize the fraction w/(h + w); the latter to minimize it.2. The duration of the isometric contraction was made considerably longer than that of the isovelocity contraction so that the (h + w) productions during the two contractions were approximately equal. 3. The PCr break-down during the working contraction was considerably greater than that during the isometric contraction.4. No detectable ATP changes occurred. 5. The break-down of PCr is sufficient to account for the work evolved: there is no reason to suppose that the work comes from an unidentified source.6. In both types of contraction extra energy is evolved that cannot be accounted for by concurrent splitting of PCr. The time course of evolution of this extra energy is similar in all types of contraction, suggesting that it may arise from a process other than cross-bridge interaction.7. The results are discussed in terms of current cross-bridge theory and muscle kinetics. The mean cycle times of a cross-bridge during working and isometric contractions are 0-12 see and 0 34 see respectively. During the working contraction cross-bridges spend about one quarter of the time attached to actin filaments.

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