A transient decrease in mitochondrial activity contributes to establish the ganglion cell fate in retina adapted for high acuity vision.

Although the plan of the retina is well conserved in vertebrates, there are considerable variations in cell type diversity and number, as well as in the organization and properties of the tissue. The high ratios of retinal ganglion cells (RGCs) to cones in primate fovea and bird retinas favor neural circuits essential for high visual acuity and color vision. The role that cell metabolism could play in cell fate decision during embryonic development of the nervous system is still largely unknown. Here, we describe how subtle changes of mitochondrial activity along the pathway converting uncommitted progenitors into newborn RGCs increase the recruitment of RGC-fated progenitors. ATOH7, a proneural protein dedicated to the production of RGCs in vertebrates, activates transcription of the Hes5.3 gene in pre-committed progenitors. The HES5.3 protein, in turn, regulates a transient decrease in mitochondrial activity via the retinoic acid signaling pathway few hours before cell commitment. This metabolic shift lengthens the progression of the ultimate cell cycle and is a necessary step for upregulating Atoh7 and promoting RGC differentiation.

The Appearance of the Warburg Effect in the Developing Avian Eye Characterized In Ovo: How Neurogenesis Can Remodel Neuroenergetics.

Purpose: The avian eye is an established model for exploring mechanisms that coordinate morphogenesis and metabolism during embryonic development. Less is known, however, about trafficking of bioenergetic and metabolic signaling molecules that are involved in retinal neurogenesis. Methods: Here we tested whether the known 3-day delayed neurogenesis occurring in the pigeon compared with the chick was associated with a deferred reshaping of eye metabolism in vivo. Developmental metabolic remodeling was explored using 1H-magnetic resonance spectroscopy of the whole eye and vitreous body, in ovo, in parallel with biochemical and molecular analyses of retinal, vitreous, and lens extracts from bird embryos. Results: Cross-species comparisons enabled us to show that a major glycolytic switch in the retina is related to neurogenesis rather than to eye growth. We further show that the temporal emergence of an interlocking regulatory cascade controlling retinal oxidative phosphorylation and glycolysis results in the exchange of lactate and citrate between the retina and vitreous. Conclusions: Our results point to the vitreous as a reservoir and buffer of energy metabolites that provides trophic support to oxidative neurons, such as retinal ganglion cells, in early development. Through its control of key glycolytic regulatory enzymes, citrate, exchanged between extracellular and intracellular compartments between the retina and vitreous, is a key metabolite in the initiation of a glycolytic switch.

Investigating Neurogenesis in Birds.

The macula and fovea make human vision unique among mammals. An understanding of the genetic network underlying the development and maintenance of this highly specialized region is instrumental to address issues about human macula-related retinopathies. The pigeon retina, unlike currently available animal models, shares numerous key characteristics of the primate macula and represents a promising new model for the study of retinal development. We provide key elements to take advantage of this new model for the study of retina and brain development. This includes precise embryo staging, transfection of genetic material (reporter plasmid, expression vectors, siRNAs) using in ovo and ex vivo electroporation, live imaging, high-resolution confocal imaging, and data layout and instructions for data analysis.

A positive feedback loop between ATOH7 and a Notch effector regulates cell-cycle progression and neurogenesis in the retina.

The HES proteins are known Notch effectors and have long been recognized as important in inhibiting neuronal differentiation. However, the roles that they play in the specification of neuronal fate remain largely unknown. Here, we show that in the differentiating retinal epithelium, the proneural protein ATOH7 (ATH5) is required for the activation of the transcription of the Hes5.3 gene before the penultimate mitosis of progenitor cells. We further show that the HES5.3 protein slows down the cell-cycle progression of Atoh7-expressing cells, thereby establishing conditions for Atoh7 to reach a high level of expression in S phase and induce neuronal differentiation prior to the ultimate mitosis. Our study uncovers how a proneural protein recruits a protein known to be a component of the Notch signaling pathway in order to regulate the transition between an initial phase of selection among uncommitted progenitors and a later phase committing the selected progenitors to neuronal differentiation.