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Corneal transplantation is the most effective clinical treatment for corneal defects, but it requires precise size of donor corneas, surgical sutures, and overcoming other technical challenges. Postoperative patients may suffer graft rejection and complications caused by sutures. Ophthalmic glues that can long-term integrate with the corneal tissue and effectively repair the focal corneal damage are highly desirable. Herein, a hybrid hydrogel consisting of porcine decellularized corneal stroma matrix (pDCSM) and methacrylated hyaluronic acid (HAMA) was developed through a non-competitive dual-crosslinking process. It can be directly filled into corneal defects with various shapes. More importantly, through formation of interpenetrating network and stable amide bonds between the hydrogel and adjacent tissue, the hydrogel manifested excellent adhesion properties to achieve suture-free repair. Meanwhile, the hybrid hydrogel not only preserved bioactive components from pDCSM, but also exhibited cornea-matching transparency, low swelling ratio, slow degradation, and enhanced mechanical properties, which was capable of withstanding superhigh intraocular pressure. The combinatorial hydrogel greatly improved the poor cell adhesion performance of HAMA, supported the viability, proliferation of corneal cells, and preservation of keratocyte phenotype. In a rabbit corneal stromal defect model, the experimental eyes treated with the hybrid hydrogel remained transparent and adhered intimately to the stroma bed with long-term retention, accelerated corneal re-epithelialization and wound healing. Giving the advantages of high bioactivity, low-cost, and good practicality, the dual-crosslinked hybrid hydrogel served effectively for long-term suture-free treatment and tissue regeneration after corneal defect.

Keratoplasty is the gold standard treatment for visual impairment caused by corneal damage. The use of suturing as the bonding method is the source of many complications following keratoplasty. Currently available corneal adhesives do not have both adequate adhesive strength and acceptable biocompatibility. Herein, we developed a photocurable bioadhesive hydrogel which was composed of gelatin methacryloyl and oxidized dextran for sutureless keratoplasty. The bioadhesive hydrogel exhibited high light transmittance, resistance to enzymatic degradation and excellent biocompatibility. It also had higher adhesive strength than commercial adhesives (fibrin glue). In a rabbit model of lamellar keratoplasty, donor corneal grafts could be closely bonded to the recipient corneal bed and remained attached for 56 days by using of this in situ photopolymerized bioadhesive hydrogel. The operated cornea maintained transparent and noninflamed. Sutureless keratoplasty using bioadhesive hydrogel allowed rapid graft re-epithelialization, typically within 7 days. In vivo confocal microscopic and histological evaluation of the operated cornea did not show any apparent abnormalities in terms of corneal cells and ultrastructure. Thus, this bioadhesive hydrogel is exhibited to be an appealing alternative to sutures for keratoplasty and other corneal surgeries.

Abstract Background To explore corneal biomechanical changes, identify related factors and determine early indicators of keratoconus (KC) development risk in allergic conjunctivitis (AC) patients. Methods A total of 50 patients, including 20 eyes without AC and 30 eyes with AC were enrolled in this study. All patients underwent a complete ocular examination, including evaluations of clinical manifestations of AC, corneal tomography and densitometry by Pentacam, corneal biomechanics by Corvis ST, and corneal and epithelial thickness mapping by RTvue optical coherence tomography (OCT). Results The index of surface variance (ISV), index of vertical asymmetry (IVA), keratoconus index (KI), index of height decentration (IHD) and Belin/Ambrosio enhanced ectasia total deviation index (BAD-D) were significantly higher in the AC group than in the non-allergic conjunctivitis (NAC) group (P

Purpose: To evaluate corneal elevation changes in patients with allergic conjunctivitis (AC) and to analyze their correlations with ocular allergy signs and corneal biomechanical alterations.Methods: Thirty patients (30 eyes) with AC and twenty normal subjects (20 eyes) were included in this prospective study. All participants underwent a complete ocular examination, including corneal tomography by Pentacam and corneal biomechanics evaluation by Corvis ST. AC patients were evaluated for their eye rubbing frequency and ocular allergic signs.Results: The elevation at the thinnest location (TE) and the central location (CE), the elevation difference at the thinnest location (TED) and the central location (CED), and the mean value of elevation difference in the central 4 mm zoom (MED) of both the anterior and posterior corneal surface were significantly higher in the AC group than in the normal group (p < 0.05 for all). In AC patients, only anterior corneal elevation parameters were positively correlated with eye rubbing frequency and ocular allergy sign severity (p < 0.05 for all), while the tomography and biomechanical index (TBI) was positively correlated with the elevation parameters of both the anterior and posterior corneal surfaces (p < 0.05 for all).Conclusion: AC patients carry an increased risk of corneal ectasia. Posterior corneal elevation parameters are sensitive and reliable predictors of keratoconus (KC) risk in AC patients.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT04299399, identifier [NCT04299399].

Background: To explore the performance of quantitative morphological and functional analysis in meibography images by an automatic meibomian glands (MGs) analyser in diagnosis and grading Meibomian Gland Dysfunction (MGD). Methods: A cross-sectional study collected 256 subjects with symptoms related to dry eye and 56 healthy volunteers who underwent complete ocular surface examination was conducted between January 1, 2019, and December 31, 2020. The 256 symptomatic subjects were classified into MGD group (n = 195) and symptomatic non-MGD group (n = 61). An automatic MGs analyser was used to obtained multi-parametric measurements in meibography images including the MGs area ratio (GA), MGs diameter deformation index (DI), MGs tortuosity index (TI), and MGs signal index (SI). Adjusted odds ratios (ORs) of the multi-parametric measurements of MGs for MGD, and the area under the receiver operating characteristic (AUC-ROC) curves of multi-parametric measurements for MGD diagnosing and grading were conducted. Findings: When consider age, sex, ocular surface condition together, the estimated ORs for DI was 1.62 (95% CI, 1.29-2.56), low-level SI was 24.34 (95% CI, 2.73-217.3), TI was 0.76(95% CI, 0.54-0.90), and GA was 0.86 (95% CI, 0.74-0.92) for MGD. The combination of DI-TI-GA-SI showed an AUC = 0.82 (P < 0.001) for discriminating MGD from symptomatic subjects. The DI had a higher AUC in identifying early-stage MGD (grade 1-2), while TI and GA had higher AUCs in moderate and advanced stages (grade 3-5). Merging DI-TI-GA showed the highest AUCs in distinguish MGD severities. Interpretation: The MGs area ratio, diameter deformation, tortuosity and signal intensity could be considered promising biomarkers for MGD diagnosis and objective grading. Funding: This work was supported by the Key-Area Research and Development Program of Guangdong Province (No. 2019B010152001), the National Natural Science Foundation of China under Grant (81901788) and Guangzhou Science and Technology Program (202002030412).

Abstract Background A worldwide lack of donor corneas demands the bioengineered corneas be developed as an alternative. The primary objective of the current study was to evaluate the efficacy of acellular porcine corneal stroma (APCS) transplantation in various types of infectious keratitis and identify risk factors that may increase APCS graft failure. Methods In this prospective interventional study, 39 patients with progressive infectious keratitis underwent therapeutic lamellar keratoplasty using APCS and were followed up for 12 months. Data collected for analysis included preoperative characteristics, visual acuity, graft survival and complications. Graft survival was evaluated by the Kaplan–Meier method and compared with the log-rank test. Results The percentage of eyes that had a visual acuity of 20/40 or better increased from 10.3% preoperatively to 51.2% at 12 months postoperatively. Twelve patients (30.8%) experienced graft failure within the follow-up period. The primary reasons given for graft failure was noninfectious graft melting (n = 5), and the other causes included recurrence of primary infection (n = 4) and extensive graft neovascularization (n = 3). No graft rejection was observed during the follow-up period. A higher relative risk (RR) of graft failure was associated with herpetic keratitis (RR = 8.0, P = 0.046) and graft size larger than 8 mm (RR = 6.5, P

Previous studies have demonstrated that orientation-specific deprivation in early life can lead to neural deficits of spatial vision in certain space, and can even result in meridional amblyopia (MA). Individuals with astigmatism are the optimal and natural models for exploring this asymmetric development of spatial vision in the human visual system. This study aims to assess the contrast sensitivity function (CSF) and EEG signals along two principal meridians in participants with regular astigmatism when being optimal optical corrected. Twelve participants with astigmatism (AST group, 20 eyes) and thirteen participants with (MA group, 19 eyes) were recruited in the current study. CSFs and spatial sweep visual evoked potentials (sVEP) were measured with vertical and horizontal sinewave gratings along two principal meridians monocularly. Area under log CSF (AULCSF), spatial frequency threshold corresponding to 80% contrast gratings (SF threshold at 80% ctr), and CSF acuity were calculated from CSF test. In addition, sVEP amplitudes and thresholds were calculated with the recursive least square method. Participants with astigmatism exhibited marked vertical-horizontal resolution disparities even after they were corrected with optimal optical corrections. CSF tests showed that AULCSF along weak meridian (measured with horizontal gratings) was lower than that along strong meridian (measured with vertical gratings) in both groups. Significant meridional disparity of CSF acuity was also found in both groups. In addition, the MA group showed larger meridional disparity compared to the AST group. Spatial sVEP thresholds also supported the existence of marked meridional disparity. Our results suggest that meridian-specific partial deprivation in early life might lead to monocularly asymmetric development of spatial vision in the human visual system. In terms of application, we tested the feasibility and reliability of adopting psychophysical and EEG scalings to investigate the asymmetric development of spatial vision related to astigmatism. These paradigms are potentially applicable to reduce and even eliminate the meridional disparity in the primary visual cortex by adopting perceptual learning or other vision-related interventions.

Ocular chemical burns are potentially blinding ocular injuries and require urgent management. Amniotic membrane (AM) transplantation is an effective surgical treatment, one of the reasons is because AM is a rich source of growth factors that can promote epithelialization and wound healing. However, growth factors will be gradually lost and insufficient after preparation process and long-time storage, leading to unsatisfactory therapeutic effects. Herein, we present a modified AM (AM-HEP) for the supplement and sustained release of growth factor by surface grafting heparin for treatment of ocular chemical burns. Heparin grafting rate and stability, microstructure, physical property, and sustained release of epithelial growth factor (EGF) of AM-HEP were characterized. Biocompatibility and ability to promote corneal epithelial cell growth and migration were evaluated and compared with a biological amnion, which is available on the market in vitro. The therapeutic effects of AM-HEP combined with EGF (AM-HEP@EGF) in vivo had been evaluated in a model of mouse corneal alkali burn. The results indicated that heparin was introduced into AM and maintain stability over 3 weeks at 37°C. The modification process of AM-HEP did not affect microstructure and physical property after comparing with non-modified AM. EGF could be combined quickly and effectively with AM-HEP; the sustained release could last for more than 14 days. AM-HEP@EGF could significantly promote corneal epithelial cell growth and migration, compared with non-modified AM and control group. Faster corneal epithelialization was observed with the transplantation of AM-HEP@EGF in vivo, compared with the untreated control group. The corneas in the AM-HEP@EGF group have less inflammation and were more transparent than those in the control group. The results from in vitro and in vivo experiments demonstrated that AM-HEP@EGF could significantly enhance the therapeutic effects. Taken together, AM-HEP@EGF is exhibited to be a potent clinical application in corneal alkali burns through accelerating corneal epithelial wound healing.

Abstract Background To determine the inter-visit variability of retinal blood flow velocities (BFVs) using a retinal function imager (RFI) in healthy young subjects. Methods Twenty eyes of 20 healthy young subjects were enrolled. RFI imaging was performed to obtain the BFVs in retinal arterioles and venules in a field measuring 7.3 × 7.3 mm2 (setting: 35 degrees) centered on the fovea, and repeated measurements were obtained on two separate days. The inter-visit variability of BFVs was assessed by the concordance correlation coefficient (CCC) and coefficient of variance (CV). Results At the first visit, the mean BFV was 3.6 ± 0.8 mm/s and 3.0 ± 0.7 mm/s in arterioles and venules, respectively, which were not significantly different from those at the second visit (the BFV of arterioles was 3.5 ± 0.8 mm/s, and the BFV of venules was 3.0 ± 0.7 mm/s, P > 0.05, respectively). The CCC was 0.72 in the BFVs of arterioles and 0.67 in venules, and the CV was 10.8% in the BFVs of arterioles and 11.0% in venules. Conclusion The inter-visit variability using the retinal function imager (RFI) with a large field of view appeared to be good and comparable to previously reported intra-visit and inter-eye variability.

The global Coronavirus Disease 2019 (COVID-19) pandemic has accelerated vaccine development at an unprecedented rate. A large population of people have received COVID-19 vaccines, while the vaccine safety data are limited. Here, we reported two cases of herpetic keratitis that occurred soon after receiving the inactivated COVID-19 vaccines. Case 1 was a 60-year-old woman who underwent penetrating keratoplasty (PKP) one year ago for corneal scarring caused by herpes simplex keratitis (HSK), and case 2 was a 51-year-old man with an unremarkable medical history. Both patients developed herpetic keratitis (HSK and varicella-zoster virus corneal endotheliitis, respectively) soon after receiving the inactivated COVID-19 vaccines (Sinovac). Herpetic keratitis was treated successfully with topical or plus oral antiviral ganciclovir. The short latency time in these two cases suggested that an inactivated COVID-19 vaccine may have a risk of triggering ocular herpes virus reactivation. Both clinicians and patients should be aware of this phenomenon. However, a causal relationship awaits confirmation.

Abstract Background Conjunctival flaps are a widely used treatment for numerous corneal ulcers that are caused by microorganismal infections. However, whether it can be performed on immune-mediated corneal ulcers is controversial. Case presentation We present two cases of Mooren’s ulcer that were treated using conjunctival flap in an attempt to prevent further corneal perforation at their local hospital. A rapid acceleration in ulcer progression was observed after a conjunctival flap was applied. Ultimately, the two patients underwent corneal transplantation, which required the postoperative use of topical immunosuppressants and resulted in a final cure. In the current report, we also discussed this incorrect surgical choice via a review of conventional interventions that are used to treat Mooren’s ulcer. Conclusions These two cases demonstrate that keratoplasty combined with topical immunosuppressants is effective in treating Mooren’s ulcer. Application of conjunctival flaps or autografting could promote progression of ulceration in Mooren’s ulcers.

Purpose. To compare the prevalence of and factors associated with Demodex brevis and Demodex folliculorum in patients with cylindrical dandruff (CD group) and healthy controls. Methods. Eyelashes were taken from 1680 patients with CD and 1700 healthy controls in China from March 2015 to May 2017. All patients underwent a complete eye examination, and Demodex spp. were counted. The prevalence was analyzed according to age, gender, and clinical features. Results. Mean patient age was 42.93 ± 16.52 (3–88) and 39.4 ± 13.6 (7–81) years old in the CD and healthy control groups, respectively. In the CD and healthy groups, the positive rate for Demodex folliculorum was 27.92% and 8.47%, respectively, while that for Demodex brevis was 31.67% and 6.65%, respectively. In the CD group, the prevalence of Demodex brevis was higher than that of Demodex folliculorum, no matter in the females (33.65% versus 29.01%) or the males (28.54% versus 23.88%) in the CD group. Moreover, the numbers of Demodex folliculorum and Demodex brevis were significantly and positively correlated with age, in both children and old patients (both P

Based on current evidence, the efficiency and safety of Descemet's membrane endothelial keratoplasty (DMEK) was compared with that of Descemet's stripping endothelial keratoplasty (DSEK).Pubmed, Embase, Web of Science, the Cochrane Database and conference abstracts were comprehensively searched for studies that compared the efficacy and safety of DMEK and DSEK. The efficacy outcome was the postoperative best-corrected visual acuity (BCVA). The safety outcomes included the postoperative endothelial cell density (ECD) and complications such as graft detachment, graft rejection, graft failure, postoperative elevated intraocular pressure (IOP), tissue loss, etc. The outcomes were pooled using random-effects models with Stata 13.0 software. Heterogeneity was qualified with Q statistic and I2/H2 statistic. Publication bias was assessed using funnel plot, Begg rank correlation test, and Egger or Horbard linear regression.19 articles were eligible, and 1124 eyes and 1254 eyes were included in the DMEK and DSEK groups, respectively. The overall pooled estimates showed a significantly better postoperative BCVA, a comparable ECD and an increased graft detachment rate in the DMEK group compared with the DSEK group (BCVA: mean difference (MD) = -0.15, 95% CI = -0.19 to -0.11, P

Exposure to sunlight has recently been postulated as responsible for the effect that more time spent outdoors protects children from myopia, while early life exposure to natural light was reported to be possibly related to onset of myopia during childhood. In this study, we had two aims: to determine whether increasing natural light exposure has a protective effect on hyperopic defocus-induced myopia, and to observe whether early postnatal exposure to natural light causes increased risk of refractive error in adolescence. Eight rhesus monkeys (aged 20-30 days) were treated monocularly with hyperopic-defocus (-3.0D lens) and divided randomly into two groups: AL group (n=4), reared under Artificial (indoor) Lighting (08:00-20:00); and NL group (n=4), exposed to Natural (outdoor) Light for 3 hours per day (11:00-14:00), and to indoor lighting for the rest of the light phase. After being reared with lenses for ca. 190 days, all monkeys were returned to unrestricted vision until the age of 3 years. Another eight age-matched monkeys, reared with unrestricted vision under artificial lighting since birth, were employed as controls. The ocular refraction, corneal curvature and axial dimensions were measured before lens-wearing (at 23±3 days of age), monthly during the light phase, and at the age of puberty (at 1185+3 days of age). During the lens-wearing treatment, infant monkeys in the NL group were more hyperopic than those in the AL group (F=5.726, P=0.032). Furthermore, the two eyes of most NL monkeys remained isometropic, whereas 3 of 4 AL monkeys developed myopic anisometropia more than -2.0D. At adolescence, eyes of AL monkeys showed significant myopic anisometropia compared with eyes of NL monkeys (AL vs NL: -1.66±0.87D vs -0.22±0.44D; P=0.002) and controls (AL vs Control: -1.66±0.87D vs -0.05±0.85D; P

To characterize the early ocular-surface changes or tear inflammatory-mediators levels following small-incision lenticule extraction (ReLEx smile) and femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK).Forty-seven myopic subjects were recruited for this prospective study. Fifteen underwent ReLEx smile and thirty-two underwent FS-LASIK. Corneal fluorescein (FL) staining, tear break-up time (TBUT), Schirmer I test (SIT), ocular surface disease index (OSDI) and central corneal sensitivity were evaluated in all participants. Tears were collected and analyzed for interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), nerve growth factor (NGF) and intercellular adhesion molecule-1 (ICAM-1) levels using multiplex magnetic beads. All measurements were preformed preoperatively and 1 day, 1 week, 1 month and 3 months postoperatively.FL scores in ReLEx smile group were lower than those of FS-LASIK group 1 week postoperatively (P = 0.010). Compared to the FS-LASIK group, longer TBUT were observed in ReLEx smile group 1 month (P = 0.029) and 3 months (P = 0.045) postoperatively. No significant differences were found in tear secretion for the two groups (P>0.05). OSDI scores were higher in FS-LASIK group 1 month after surgery (P = 0.020). Higher central corneal sensitivity was observed in ReLEx smile group 1 week, 1 month and 3 months (P0.05). Moreover, IL-6 and NGF levels correlated with ocular surface changes after ReLEx smile or FS-LASIK.In the early postoperative period, ReLEx smile results in milder ocular surface changes than FS-LASIK. Furthermore, the tear inflammatory mediators IL-6 and NGF may play a crucial role in the ocular surface healing process following ReLEx smile and FS-LASIK.

Neural cell fate specification is well understood in the embryonic cerebral cortex, where the proneural genes Neurog2 and Ascl1 are key cell fate determinants. What is less well understood is how cellular diversity is generated in brain tumors. Gliomas and glioneuronal tumors, which are often localized in the cerebrum, are both characterized by a neoplastic glial component, but glioneuronal tumors also have an intermixed neuronal component. A core abnormality in both tumor groups is overactive RAS/ERK signaling, a pro-proliferative signal whose contributions to cell differentiation in oncogenesis are largely unexplored. We found that RAS/ERK activation levels differ in two distinct human tumors associated with constitutively active BRAF. Pilocytic astrocytomas, which contain abnormal glial cells, have higherERKactivation levels than gangliogliomas, which contain abnormal neuronal and glial cells. Using in vivo gain of function and loss of function in the mouse embryonic neocortex, we found that RAS/ERK signals control a proneural genetic switch, inhibiting Neurog2 expression while inducing Ascl1, a competing lineage determinant. Furthermore, we found that RAS/ERK levels control Ascl1's fate specification properties in murine cortical progenitors-at higher RAS/ERK levels, Ascl1+ progenitors are biased toward proliferative glial programs, initiating astrocytomas, while at moderate RAS/ERK levels, Ascl1 promotes GABAergic neuronal and less glial differentiation, generating glioneuronal tumors. Mechanistically, Ascl1 is phosphorylated by ERK, and ERK phosphoacceptor sites are necessary for Ascl1's GABAergic neuronal and gliogenic potential. RAS/ERK signaling thus acts as a rheostat to influence neural cell fate selection in both normal cortical development and gliomagenesis, controlling Neurog2-Ascl1 expression and Ascl1 function. [ABSTRACT FROM AUTHOR]

The neocortex is comprised of six neuronal layers that are generated in a defined temporal sequence. While extrinsic and intrinsic cues are known to regulate the sequential production of neocortical neurons, how these factors interact and function in a coordinated manner is poorly understood. The proneural gene Neurog2 is expressed in progenitors throughout corticogenesis, but is only required to specify early-born, deep-layer neuronal identities. Here, we examined how neuronal differentiation in general and Neurog2 function in particular are temporally controlled during murine neocortical development. We found that Neurog2 proneural activity declines in late corticogenesis, correlating with its phosphorylation by GSK3 kinase. Accordingly, GSK3 activity, which is negatively regulated by canonical Wnt signaling, increases over developmental time, while Wnt signaling correspondingly decreases. When ectopically activated, GSK3 inhibits Neurog2-mediated transcription in cultured cells and Neurog2 proneural activities in vivo. Conversely, a reduction in GSK3 activity promotes the precocious differentiation of later stage cortical progenitors without influencing laminar fate specification. Mechanistically, we show that GSK3 suppresses Neurog2 activity by influencing its choice of dimerization partner, promoting heterodimeric interactions with E47 (Tcfe2a), as opposed to Neurog2-Neurog2 homodimer formation, which occurs when GSK3 activity levels are low. At the functional level, Neurog2-E47 heterodimers have a reduced ability to transactivate neuronal differentiation genes compared with Neurog2-Neurog2 homodimers, both in vitro and in vivo. We thus conclude that the temporal regulation of Neurog2-E47 heterodimerization by GSK3 is a central component of the neuronal differentiation "clock" that coordinates the timing and tempo of neocortical neurogenesis in mouse. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 37-year-old woman who was diagnosed with mild hyperemia and conjunctival papillary reaction that is consistent with allergic conjunctivitis and was found to have protruding iris collarettes.

Lipopolysaccharide (LPS)‑induced keratitis is a progressive infectious ocular disease in which innate inflammatory responses often cause clinical tissue damage and vision loss. The present study aimed to investigate the effects of tacrolimus, an effective immunomodulator, on LPS‑induced innate immune responses. The effects of tacrolimus on the apoptotic rate and viability of human corneal epithelial cells (HCECs), polymorphonuclear neutrophils (PMNs) and monocytes (THP‑1 cells) were examined using flow cytometry and MTT assays. Subsequently, the role of tacrolimus on LPS‑induced inflammation in HCECs, PMNs and THP‑1 cells w as evaluated b y d etecting t he expression l evels o f pro‑inflammatory cytokines, including interleukin (IL)‑1β, IL‑6 and matrix metallopeptidase 9; anti‑inflammatory cytokines, including IL‑10 and transforming growth factor‑β; and proangiogenic factors, including vascular endothelial growth factor and tumor necrosis factor‑α using quantitative polymerase chain reaction. The results demonstrated that tacrolimus had good biocompatibility with HCECs, while promoting apoptosis and decreasing the viability of PMNs and THP‑1 cells. Furthermore, tacrolimus effectively reduced the expression levels of pro‑inflammatory cytokines and increased anti‑inflammatory cytokines in LPS‑induced keratitis in vitro. Notably, tacrolimus decreased the levels of proangiogenic factors, which are highly increased following LPS stimulation. Conclusively, tacrolimus appears to be a safe and effective treatment to suppress neutrophil and monocyte activity, modulate the balance of pro‑/anti‑inflammatory cytokines, and reduce the inflammatory response and angiogenic activity in LPS‑induced bacterial keratitis. [ABSTRACT FROM AUTHOR]

Imprinted genes are dosage sensitive, and their dysregulated expression is linked to disorders of growth and proliferation, including fetal and postnatal growth restriction. Common sequelae of growth disorders include neurodevelopmental defects, some of which are indirectly related to placental insufficiency. However, several growth-associated imprinted genes are also expressed in the embryonic CNS, in which their aberrant expression may more directly affect neurodevelopment. To test whether growth-associated genes influence neural lineage progression, we focused on the maternally imprinted gene Zac1. In humans, either loss or gain of ZAC1 expression is associated with reduced growth rates and intellectual disability. To test whether increased Zac1 expression directly perturbs neurodevelopment, we misexpressed Zac1 in murine neocortical progenitors. The effects were striking: Zac1 delayed the transition of apical radial glial cells to basal intermediate neuronal progenitors and postponed their subsequent differentiation into neurons. Zac1 misexpression also blocked neuronal migration, with Zac1-overexpressing neurons pausing more frequently and forming fewer neurite branches during the period when locomoting neurons undergo dynamic morphological transitions. Similar, albeit less striking, neuronal migration and morphological defects were observed on Zac1 knockdown, indicating that Zac1 levels must be regulated precisely. Finally, Zac1 controlled neuronal migration by regulating Pac1 transcription, a receptor for the neuropeptide pituitary adenylate cyclase-activating polypeptide (PA CAP). Pac1 and Zac1 loss- and gain-of-function presented as phenocopies, and overexpression of Pac1 rescued the Zac1 knockdown neuronal migration phenotype. Thus, dysregulated Zac1 expression has striking consequences on neocortical development, suggesting that misexpression of this transcription factor in the brain in certain growth disorders may contribute to neurocognitive deficits. [ABSTRACT FROM AUTHOR]

The three-layered piriform cortex, an integral part of the olfactory system, processes odor information relayed by olfactory bulb mitral cells. Specifically, mitral cell axons form the lateral olfactory tract (LOT) by targeting lateral olfactory tract (lot) guidepost cells in the piriform cortex. While lot cells and other piriform cortical neurons share a pallial origin, the factors that specify their precise phenotypes are poorly understood. Here we show that in mouse, the proneural genes Neurog1 and Neurog2 are coexpressed in the ventral pallium, a progenitor pool that first gives rise to Cajal-Retzius (CR) cells, which populate layer I of all cortical domains, and later to layer II/III neurons of the piriform cortex. Using loss-of-function and gain-of-function approaches, we find that Neurog1 has a unique early role in reducing CR cell neurogenesis by tempering Neurog2's proneural activity. In addition, Neurog1 and Neurog2 have redundant functions in the ventral pallium, acting in two phases to first specify a CR cell fate and later to specify layer II/III piriform cortex neuronal identities. In the early phase, Neurog1 and Neurog2 are also required for lot cell differentiation, which we reveal are a subset of CR neurons, the loss of which prevents mitral cell axon innervation and LOT formation. Consequently, mutation of Trp73, a CR-specific cortical gene, results in lot cell andLOTaxon displacement. Neurog1 and Neurog2 thus have unique and redundant functions in the piriform cortex, controlling the timing of differentiation of early-born CR/lot cells and specifying the identities of later-born layer II/III neurons. [ABSTRACT FROM AUTHOR]