未经证实:Notch通路是发育过程中神经元生成的基础。我们先前报道过,编码Notch的Delta样配体1(Dll1lacZ)的基因的无效等位基因杂合的成年小鼠在黑质致密体中的神经元密度降低。本工作的目的是评估这种改变是否扩展到其他大脑结构以及受影响受试者的行为后果。
UNASSIGNED:将不同年龄的Dll1/lacZ胚胎和小鼠的大脑与野生型(WT)对应物进行了表型比较。之后,进行脑组织学分析,然后测定组织切片中的神经细胞标志物.通过对Dll1+/lacZ和WT小鼠应用不同的行为测试来诊断神经缺陷。
UNASSIGNED:与WT同窝动物相比,Dll1/lacZ小鼠的脑重量和大小显着降低(即,小头畸形),出生后早期发现的表型。有趣的是,扩大的心室(即,脑积水)是Dll1单倍体不足小鼠大脑的常见特征。在细胞层面,一般的细胞密度和几个大脑区域的神经元数量,包括大脑皮层和海马体,与WT小鼠的那些区域相比,Dll1+/lacZ小鼠的减少。此外,特别是在Dll1/lacZ小鼠的成年齿状回中发现了较少的神经干细胞,但在脑室下区没有发现。在出生后早期年龄(P7-P24)检测到的高髓鞘形成水平是Dll1/lacZ小鼠的额外渗透表型,观察结果与早熟少突胶质细胞分化一致。在应用了一组行为测试后,检测到轻度的神经系统改变导致运动行为的改变和对象分类的缺陷。
UNASSIGNED:我们的观察表明,Dll1单倍体功能不全限制了大脑发育过程中的Notch信号传导,一方面,导致脑细胞密度降低,并导致小头畸形和脑积水表型,另一方面,改变出生后的髓鞘形成过程。这些缺陷的严重程度可能会达到影响正常大脑功能的水平。因此,Dll1单倍体功能不全是一个危险因素,使大脑容易发生功能异常。
UNASSIGNED: The Notch pathway is fundamental for the generation of neurons during development. We previously reported that adult mice heterozygous for the null allele of the gene encoding the Delta-like ligand 1 for Notch (Dll1lacZ ) have a reduced neuronal density in the substantia nigra pars compacta. The aim of the present work was to evaluate whether this alteration extends to other brain structures and the behavioral consequences of affected subjects.
UNASSIGNED: Brains of Dll1 +/lacZ embryos and mice at different ages were phenotypically compared against their wild type (WT) counterpart. Afterwards, brain histological analyses were performed followed by determinations of neural cell markers in tissue slices. Neurological deficits were diagnosed by applying different behavioral tests to Dll1 +/lacZ and WT mice.
UNASSIGNED: Brain weight and size of Dll1 +/lacZ mice was significantly decreased compared with WT littermates (i.e., microcephaly), a phenotype detected early after birth. Interestingly, enlarged ventricles (i.e., hydrocephalus) was a common characteristic of brains of Dll1 haploinsufficient mice since early ages. At the cell level, general cell density and number of neurons in several brain regions, including the cortex and hippocampus, of Dll1 +/lacZ mice were reduced as compared with those regions of WT mice. Also, fewer neural stem cells were particularly found in the adult dentate gyrus of Dll1 +/lacZ mice but not in the subventricular zone. High myelination levels detected at early postnatal ages (P7-P24) were an additional penetrant phenotype in Dll1 +/lacZ mice, observation that was consistent with premature oligodendrocyte differentiation. After applying a set of behavioral tests, mild neurological alterations were detected that caused changes in motor behaviors and a deficit in object categorization.
UNASSIGNED: Our observations suggest that Dll1 haploinsufficiency limits Notch signaling during brain development which, on one hand, leads to reduced brain cell density and causes microcephaly and hydrocephalus phenotypes and, on the other, alters the myelination process after birth. The severity of these defects could reach levels that affect normal brain function. Therefore, Dll1 haploinsufficiency is a risk factor that predisposes the brain to develop abnormalities with functional consequences.