Loss of MAP3K1 enhances proliferation and apoptosis during retinal development

Abstract

SUMMARYPrecise coordination of progenitor cell proliferation and differentiation is essential for proper organ morphogenesis and function during mammalian development. The mitogen-activated protein kinase kinase kinase 1 (MAP3K1) has a well-established role in anterior eyelid development, as Map3k1-knockout mice have defective embryonic eyelid closure and an 'eye-open at birth' (EOB) phenotype. Here, we show that MAP3K1 is highly expressed in the posterior of the developing eye and is required for retina development. The MAP3K1-deficient mice exhibit increased proliferation and apoptosis, and Müller glial cell overproduction in the developing retinas. Consequently, the retinas of these mice show localized rosette-like arrangements in the outer nuclear layer, and develop abnormal vascularization, broken down retinal pigment epithelium, photoreceptor loss and early onset of retinal degeneration. Although the retinal defect is associated with increased cyclin D1 and CDK4/6 expression, and RB phosphorylation and E2F-target gene upregulation, it is independent of the EOB phenotype and of JNK. The retinal developmental defect still occurs in knockout mice that have undergone tarsorrhaphy, but is absent in compound mutant Map3k1 Jnk1-/-and Map3k1 Jnk2+/-mice that have EOB and reduced JNK signaling. Our results unveil a novel role for MAP3K1 in which it crosstalks with the cell cycle regulatory pathways in the prevention of retina malformation and degeneration.

Matrix metalloproteinase 2 and membrane type 1 matrix metalloproteinase co‐regulate axonal outgrowth of mouse retinal ganglion cells

“…Acridine orange experiments revealed apoptotic cells in all explants, including controls, which should not be surprising as apoptosis is a naturally occurring process in the developing postnatal mouse retina (Williams et al 1990;Mongan et al 2011). None of the inhibitors increased the number of dying cells, indicating that the phenotypes observed after compound administration, that is, a reduced axonal outgrowth, were not because of a general toxic effect of the MMP-inhibiting compounds.…”

“…; Mongan et al . ). None of the inhibitors increased the number of dying cells, indicating that the phenotypes observed after compound administration, that is, a reduced axonal outgrowth, were not because of a general toxic effect of the MMP‐inhibiting compounds.…”

S1P transporter SPNS2 regulates proper postnatal retinal morphogenesis

“…Morphology was analyzed at P7 by H&E staining. For the artificial EOB model, the surgical procedure was designed according to a previous study (40). Neonatal spns2 +/+ rats were cryoanesthetized, and eyelid was carefully separated.…”

Defective eyelid leading edge cell migration in C57BL/6-corneal opacity mice with an “eye open at birth” phenotype

“…A previous study showed that impaired cell proliferation was associated with eyelid closure (Mongan et al, 2011). Other studies also reported that apoptosis affects this process.…”