In contrast to cyclin D1 nulls (cD1 -/-), mice without cyclin D2 (cD2 -/-) lack cerebellar stellate interneurons; the reason for this is unknown. In the present study in cortex, we found a disproportionate loss of parvalbumin (PV) interneurons in cD2 -/-mice. This selective reduction in PV subtypes was associated with reduced frequency of GABA-mediated inhibitory postsynaptic currents in pyramidal neurons, as measured by voltage-clamp recordings, and increased cortical sharp activity in the EEGs of awake-behaving cD2 -/-mice. Cell cycle regulation was examined in the medial ganglionic eminence (MGE), the major source of PV interneurons in mouse brain, and differences between cD2 -/-and cD1 -/-suggested that cD2 promotes subventricular zone (SVZ) divisions, exerting a stronger inhibitory influence on the p27 Cdk-inhibitor (Cdkn1b) to delay cell cycle exit of progenitors. We propose that cD2 promotes transit-amplifying divisions in the SVZ and that these ensure proper output of at least a subset of PV interneurons.

No abstract

S phase entry, I.e. start of DNA replication, Is a crucial step in proliferation. Inhibition of S phase entry correlates with Inbibition of hypusine formation, an event affecting only the eukaryotie Initiation factor $A (elF4A), Its hypuslnecontalning sequence wus postulated to authorize polysomal utilization of specific trauscripts for proteins necessary to enable DNA replication. Using ndmodne to reversibly suppress the hyposinc-forming deoxyhypusyi hydmxylase (E.C. 1.1¢99.29) in cells while differentially displaying their polysomal versus non-polysemal mRNA popolations, we report the detection and cla~!fleation of several mRNA species that indeed disappear from and reappear at !lo1-ysomes in con~rt with inhibition and d_!s!nhibition, respectively, of hypusine formation. Based on initial sequence data, two trauslationally controlled enzymes, both critical for proliferation, are identified us candicate wodncts of such mRNAs, methionine adenosyitrausferuse (E.C 2.$.1.6) and cytochrome-c oxiduse 0gC 1.9.3.1) subunit 1. The existence of such potative hyposinedependent messenger nnclde adds (/O, mas) prevides the basis for a proposal on their molecular function in onset of multiplication.Key words: Post-translational modification; eIF-5A; Hypusine; Cell cycle control; Translational control; mRNA I, IntroductionThe unique amino acid hypusine [~-(4-amino-2(R).hydroxybutyl)-t.-lysine] is formed post-translationally by the sequential action of deoxyhypusyl synthase (DOHS) and deoxyhypusyl hydroxylase (DOHH) on a single lysyl residue in only one cellular protein, the eukaryotic initiation factor 5A (elF-SA) [I-3]. The hypusine-containing domain shows remarkable interspecies conservation, and a sequence of 12 amino acids containing the hypusine residue has been strictly conserved throughout eukaryotic evolution, from fungi to plants, insects, and mammals [3]. Hypusine formation, which has not been demonstrated in prokaryotes [2], is an absolute requirement for growth of $. cerevesiae [4], and a number of *Correspondin8 authors, Fax: (I) (212) 746 0300 and Fax: (I) (212) 746 6382, respectively.'For Stephen Biko (December 18, 1944.-September 12, 1977.reports have established correlations between hypusine formation and the proliferation of eukaryotic cells (see [2,3]). However, the exact physiological function of this presumed translation initiatic~n factor is unknown, and at present it even is unclear whether elF-SA functions at the pretranslational and/ or the translational level [3].Deoxyhypusyl hydroxylase (E.C. 1.14.99.29), which catalyses the final step of hypusine biosynthesis, is apparently related [5,6] to other protein hydroxy]ating enzymes such as prolyl 4-hydroxylase (E.C 1.14.11.2) [7] and is effectively inhibited by mimosine (3-(N-(3-hydroxypyridin-4-one))-2[S]-aminopropionic acid), both in vitro and in culture [3]. This coincides with proliferative arrest in the late GI phase ofthe cell cycle [3,[8][9][10][11]. Fast recovery ofcellular DOHH activity occurs upon mimo,,;ine removal, an effect parallele...

No abstract

11beta-Hydroxylase deficiency is a common form of congenital adrenal hyperplasia causing virilization of the female fetus and hypertension. DNA analysis of the gene (CYP11B1) encoding 11beta-hydroxylase has been reported previously to be effective in the prenatal diagnosis of one affected female fetus. In that case, prenatal treatment with dexamethasone resulted in normal female genitalia. We now report five new pregnancies that underwent prenatal diagnosis for 11beta-hydroxylase deficiency. In the first family, the proband is homozygous for a T318M mutation and all fetuses from four subsequent pregnancies are carriers. In a second family, the mother is homozygous for a A331V mutation and was started on dexamethasone, but identification of a homozygous normal fetus led to the discontinuation of treatment. In another family, the fetus was a male homozygous for R384Q and treatment was discontinued. Lastly, a novel G444D mutation in exon 8 was identified and proven to reduce 11beta-hydroxylase activity.

No abstract

No abstract

No abstract