Diffuse overexpression of p16INK4a in basal and parabasal cells of cervical epithelium is a hallmark of human papillomavirus‐mediated transformation. Focal p16INK4a expression is occasionally observed in nondysplastic epithelium. In normal cells, expression of p16INK4a triggers cell cycle arrest. However, cells undergoing transformation in intraepithelial lesions actively proliferate. To prove that the different expression patterns of p16INK4a, i.e., focal versus diffuse, reflect biologically different entities, we hypothesized that p16INK4a‐positive cells in epithelia displaying focal p16INK4a expression pattern do not coexpress proliferation‐associated Ki‐67 protein, while p16INK4a‐positive cells in lesions with diffuse p16INK4a expression may do. A total of 138 cervical cone biopsies were stained for the expression of p16INK4a and Ki‐67 using a primary antibody cocktail. All metaplastic lesions (n = 21) displayed focal staining for p16INK4a, and in all of these lesions p16INK4a‐positive cells were found to be negative for Ki‐67 expression. Diffuse expression of p16INK4a was observed in 12/21 (57.1%) cervical intraepithelial neoplasia (CIN) 1 lesions, all of them simultaneously showed Ki‐67 immunoreactivity in a large proportion of p16INK4a‐positive cells. Seventeen of 23 (73.9%) CIN2 lesions and all 27 (100%) CIN3/carcinoma in situ (CIS) as well as all 46 (100%) carcinoma cases displayed diffuse and combined expression of p16INK4a and Ki‐67. Coexpression of Ki‐67 and p16INK4a in the same cell is entirely restricted to cervical lesions displaying diffuse p16INK4a expression, whereas in lesions with focal p16INK4a expression, p16INK4a‐expressing cells are negative for Ki‐67. Thus, diffuse expression of p16INK4a reflects lesions with proliferation‐competent cells, while p16INK4a‐expressing cells associated with focal expression patterns are cell cycle arrested.

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We have investigated the influence of meningeal cells on the development of the cerebellum by destroying these cells with 6-hydroxydopamine in hamsters of different ages. The ensuing foliation and lamination disruption in the cerebellar vermis is attributed to a disintegration of the cerebellar surface and a disorganization of the glial scaffold of the cerebellar cortex due to a loss of meningeal-glial interaction in stabilizing the extracellular matrix at the glia limitans superficialis (v. Knebel Doeberitz et al. 1986, Neuroscience 17:409-426). The severity of these cerebellar defects is correlated with the ontogenetic stage at which meningeal cells are destroyed, being greatest after treatment at postnatal day 1 and decreasing thereafter until day 5 and beyond, when no abnormalities occur, although all meningeal cells are destroyed throughout. The absence of cerebellar defects after destruction of meningeal cells at day 5 or later is associated firstly with the end of the period of branching morphogenesis of the cerebellum when all folial primordia are established, and, secondly, with the maturation of the glia limitans superficialis. These findings indicate that meningeal cells stabilize the cerebellar surface and glial scaffold over a critical period that ends, when the pattern of cerebellar foliation is established, and when the glia limitans superficialis has reached a mature state. Beyond this stage glial end-feet alone are sufficient to maintain the epithelial integrity of the cerebellum.

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