Molecular Fingerprint and Developmental Regulation of the Tegmental GABAergic and Glutamatergic Neurons Derived from the Anterior Hindbrain.

Tegmental nuclei in the ventral midbrain and anterior hindbrain control motivated behavior, mood, memory, and movement. These nuclei contain inhibitory GABAergic and excitatory glutamatergic neurons, whose molecular diversity and development remain largely unraveled. Many tegmental neurons originate in the embryonic ventral rhombomere 1 (r1), where GABAergic fate is regulated by the transcription factor (TF) Tal1. We used single-cell mRNA sequencing of the mouse ventral r1 to characterize the Tal1-dependent and independent neuronal precursors. We describe gene expression dynamics during bifurcation of the GABAergic and glutamatergic lineages and show how active Notch signaling promotes GABAergic fate selection in post-mitotic precursors. We identify GABAergic precursor subtypes that give rise to distinct tegmental nuclei and demonstrate that Sox14 and Zfpm2, two TFs downstream of Tal1, are necessary for the differentiation of specific tegmental GABAergic neurons. Our results provide a framework for understanding the development of cellular diversity in the tegmental nuclei.

Corrigendum: Dusp16 Deficiency Causes Congenital Obstructive Hydrocephalus and Brain Overgrowth by Expansion of the Neural Progenitor Pool.

[This corrects the article on p. 372 in vol. 10, PMID: 29170629.].

Dusp16 Deficiency Causes Congenital Obstructive Hydrocephalus and Brain Overgrowth by Expansion of the Neural Progenitor Pool.

Hydrocephalus can occur in children alone or in combination with other neurodevelopmental disorders that are often associated with brain overgrowth. Despite the severity of these disorders, the molecular and cellular mechanisms underlying these pathologies and their comorbidity are poorly understood. Here, we studied the consequences of genetically inactivating in mice dual-specificity phosphatase 16 (Dusp16), which is known to negatively regulate mitogen-activated protein kinases (MAPKs) and which has never previously been implicated in brain development and disorders. Mouse mutants lacking a functional Dusp16 gene (Dusp16-/-) developed fully-penetrant congenital obstructive hydrocephalus together with brain overgrowth. The midbrain aqueduct in Dusp16-/- mutants was obstructed during mid-gestation by an expansion of neural progenitors, and during later gestational stages by neurons resulting in a blockage of cerebrospinal fluid (CSF) outflow. In contrast, the roof plate and ependymal cells developed normally. We identified a delayed cell cycle exit of neural progenitors in Dusp16-/- mutants as a cause of progenitor overproliferation during mid-gestation. At later gestational stages, this expanded neural progenitor pool generated an increased number of neurons associated with enlarged brain volume. Taken together, we found that Dusp16 plays a critical role in neurogenesis by balancing neural progenitor cell proliferation and neural differentiation. Moreover our results suggest that a lack of functional Dusp16 could play a central role in the molecular mechanisms linking brain overgrowth and hydrocephalus.

The effect of cataract surgery and IOL implantation on the magnification of a fundus photograph: a pilot study.

PURPOSE: The goal was to determine the effect of cataract surgery-induced change in ametropia and anterior chamber depth on the magnification of a fundus photograph. METHODS: Fundus photographs were taken from 11 subjects undergoing cataract surgery and intraocular lens (IOL) implantation before and after surgery with a telecentric Zeiss and Topcon fundus cameras. The distance between two distinct fundus landmarks, i.e. two crossings of retinal vessels, was measured before and after surgery, and the results were compared to axial length and surgery-induced change in ametropia and anterior chamber depth. In addition, the change in the conversion factor of Topcon fundus camera was calculated and its correlation to axial length, change in ametropia and anterior chamber depth was analysed. Further, the change in the mathematical location of P', i.e. the second principal point of the eye in the formula of Bennett et al. (1994), was calculated. RESULTS: Cataract surgery and IOL implantation did not significantly influence the magnification of a fundus photograph taken with a telecentric Zeiss or Topcon fundus camera even when ametropia changed markedly. Axial length and anterior chamber depth did not correlate with change in the magnification of a fundus photograph. The average change in the mathematical location P' due to surgery was -39.4%, SD 0.33. CONCLUSION: Fundus photographs taken with a telecentric Zeiss or Topcon fundus camera can be reliably used to follow the size of fundus landmarks even if ametropia and anterior chamber depth are changed after cataract surgery and IOL implantation.

Determining the size of retinal features in prematurely born children by fundus photography.

PURPOSE: The purpose was to study the effect of prematurity on the macula-disc centre distance and whether it could be used as a reference tool for determining the size of retinal features in prematurely born children by fundus photography. METHODS: The macula-disc centre distance of the left eye was measured in pixels from digital fundus photographs taken from 27 prematurely born children aged 10-11 years with Topcon fundus camera. A conversion factor for Topcon fundus camera (194.98 pixel/mm for a 50° lens) was used to convert the results in pixels into metric units. RESULTS: The macula-disc centre distance was 4.74 mm, SD 0.29. No correlation between ametropia and the macula-disc centre distance was found (r = -0.07, p > 0.05). One child (subject 20) had high myopia and retinopathy of prematurity (ROP), and the macula-disc centre distance was longer than average (6.35 mm). DISCUSSION: The macula-disc centre distance in prematurely born children at the age of 10-11 years provides an easy-to-use reference tool for evaluating the size of retinal features on fundus photographs. However, if complications of ROP, for example temporal macular dragging or high ametropia, are present, the macula-disc centre distance is potentially altered and a personal macula-disc centre distance should be determined and used as a refined reference tool.

Clinical verification of the formula of Bennett et al. (1994) of determining the size of retinal features by fundus photography.

PURPOSE: To clinically verify the formula of Bennett et al. (Graefes Arch Clin Exp 1994; 232: 361) of determining the size of retinal features and to study the previously unknown conversion factor of Topcon fundus camera. METHODS: Fundus photographs were taken from 17 healthy volunteers with Topcon and telecentric Zeiss fundus cameras. The macula-disc centre distance was measured from Zeiss fundus photographs in metric units using the formula of Bennett et al. (Graefes Arch Clin Exp 1994; 232: 361). The conversion factor of Topcon fundus camera and the macula-disc centre distance in degrees were calculated. The latter was further used to calculate the theoretical location of the blind spot. The results of 12 participants were compared to the location of their physiological blind spot determined with visual field examination by octopus custom-made blind spot visual field program. RESULTS: The theoretical location of the blind spot correlated well with the corresponding location of the physiological blind spot in the visual field. The magnification of Topcon fundus camera was close to a constant, and thus, the previously unknown conversion factor could be determined. CONCLUSIONS: The location of the physiological blind spot in the visual field can be derived from fundus photographs using the formula of Bennett et al. (Graefes Arch Clin Exp 1994; 232: 361), proving it to give a close approximation of the size of retinal features. Furthermore, the conversion factor of Topcon fundus camera was close to a constant, and thus, it can be considered to function close to telecentric design.