Math5 is required for both early retinal neuron differentiation and cell cycle progression.
CNS progenitors choose a fate, exit mitosis and differentiate. Basic helix-loop-helix (bHLH) transcription factors are key regulators of neurogenesis, but their molecular mechanisms remain unclear. In the mouse retina, removal of the bHLH factor Math5 (Atoh7) causes the loss of retinal ganglion cells (RGCs) and appearance of excess cone photoreceptors. Here, we show a simultaneous requirement for Math5 in retinal neuron formation and cell cycle progression. At embryonic day E11.5, Math5-/- cells are unable to assume the earliest fates, particularly that of an RGC, and instead adopt the last fate as Müller glia. Concurrently, the loss of Math5 causes mitotically active retinal progenitors to undergo aberrant cell cycles. The drastic fate shift of Math5-/- cells correlates with age-specific alterations in p27/Kip1 expression and an inability to become fully postmitotic. Finally, Math5 normally suppresses NeuroD1 within Math5-expressing cells and inhibits Ngn2 expression and cone photoreceptor genesis within separate cell populations. Thus, Math5 orchestrates neurogenesis in multiple ways, regulating both intrinsic and extrinsic processes.
Le
Tien T
TT
Division of Developmental Biology, Children's Hospital Research Foundation, Departments of Pediatrics and Ophthalmology University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-7007, USA.
Wroblewski
Emily
E
Patel
Sima
S
Riesenberg
Amy N
AN
Brown
Nadean L
NL
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D004622:Embryo, Mammalian; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D012160:Retina / Q000166:cytology*; D013234:Stem Cells
D051792:Basic Helix-Loop-Helix Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D009419:Nerve Tissue Proteins; C117638:Atoh7 protein, mouse; C501008:Neurod1 protein, mouse; C102938:Neurog2 protein, mouse