Neuronal Differentiation and Patterning inXenopus: The Role of cdk5 and a Novel Activator Xp35.2

Abstract

Cdk5, a member of the cyclin-dependent kinase family, has been shown to play an important role in development of the central nervous system in mammals when partnered by its activator p35. Here we describe the cloning and characterization of a novel activator of cdk5 in Xenopus, Xp35.2. Xp35.2 is expressed during development initially in the earliest differentiating primary neurons in the neural plate and then later in differentiating neural tissue of the brain. This is in contrast to the previously described Xenopus cdk5 activator Xp35.1 which is expressed over the entire expanse of the neural plate in both proliferating and differentiating cells. Expression of both Xp35.1 and Xp35.2 and activation of cdk5 kinase occur when terminal neural differentiation is induced by neurogenin and neuro D overexpression but not when only early stages of neural differentiation are induced by noggin. Moreover, blocking cdk5 kinase activity specifically results in disruption and reduction of the embryonic eye where cdk5 and its Xp35 activators are expressed. Thus, cdk5/p35 complexes function in aspects of neural differentiation and patterning in the early embryo and particularly in formation of the eye.

Cloning and characterization of zebrafish (Danio rerio) cyclin-dependent kinase 5

“…The presence of cdk5 mRNA in zebrafish embryos much earlier than muscle or neuronal differentiation in contrast to its late expression in Xenopus [17] implies a function devoted to early developmental processes including a possible role in neurogenesis. Subsequent ubiquitous expression of cdk5 mRNA in the brain, eyes and body axis is consistent with its well-established function in neuromuscular development and differentiation [5,17,18,23]. However, in spite of the reduction in cdk5 protein level in the cdk5 siRNA-injected embryos, no delays in development or gross morphological abnormalities were observed as compared to the control embryos.…”

“…The zebrafish cdk5 is strikingly homologous (at ~ 97%) to all vertebrate cdk5s, a conservation consistent with the view that this kinase plays a major role in development and function of the vertebrate nervous systems. Compared to other vertebrates, particularly closely related Xenopus [17,18,21], cdk5 mRNA is expressed very early before the midblastula transition its expression remaining relatively constant up to 72 hrs of development in zebrafish. The presence of cdk5 mRNA in zebrafish embryos much earlier than muscle or neuronal differentiation in contrast to its late expression in Xenopus [17] implies a function devoted to early developmental processes including a possible role in neurogenesis.…”

“…a dominant-negative mutant of cdk5 inhibits neurite outgrowth [15]. In Xenopus, cdk5 plays a role in eye and muscle development and has two p35 activators [6,17,18]. …”

Extraneuronal roles of cyclin‐dependent kinase 5

“…microphthalmia, disruption of the eye structure and lens malformation. (34) Since these phenotypes can be rescued by concomitant injection of wt-Cdk5, the abnormalities are indicative of inhibition of endogenous Cdk5 activity. Cdk5 has further been demonstrated in visceral glomerular epithelial cells (podocytes) during glomerulogenesis.…”

Phosphorylation of Pak1 by the p35/Cdk5 Kinase Affects Neuronal Morphology

“…Both p35 and Cdk5 are essential for the proper development of the Drosophila and Xenopus CNS in which alterations in kinase activity affect differentiation and the accuracy of axonal patterning (15,16). A role for the p35/ Cdk5 kinase has also been suggested in regulating synapses (17)(18)(19)(20)(21), whereas deregulation of its activity may play a part in several neuropathologies, especially Alzheimer's (22,23).…”