Abstract
The vertebrate cerebellum arises at the dorsal part of rhombomere 1, induced by signals from the isthmic organizer. Two major cerebellar neuronal subtypes, granule cells (excitatory) and Purkinje cells (inhibitory), are generated from the anterior rhombic lip and the ventricular zone, respectively. This regionalization and the way it develops are shared in all extant jawed vertebrates (gnathostomes). However, very little is known about early evolution of the cerebellum. The lamprey, an extant jawless vertebrate lineage or cyclostome, possesses an undifferentiated, plate-like cerebellum, whereas the hagfish, another cyclostome lineage, is thought to lack a cerebellum proper. In this study, we found that hagfish Atoh1 and Wnt1 genes are co-expressed in the rhombic lip, and Ptf1a is expressed ventrally to them, confirming the existence of r1’s rhombic lip and the ventricular zone in cyclostomes. In later stages, lamprey Atoh1 is downregulated in the posterior r1, in which the NeuroD increases, similar to the differentiation process of cerebellar granule cells in gnathostomes. Also, a continuous Atoh1-positive domain in the rostral r1 is reminiscent of the primordium of valvula cerebelli of ray-finned fishes. Lastly, we detected a GAD-positive domain adjacent to the Ptf1a-positive ventricular zone in lampreys, suggesting that the Ptf1a-positive cells differentiate into some GABAergic inhibitory neurons such as Purkinje and other inhibitory neurons like in gnathostomes. Altogether, we conclude that the ancestral genetic programs for the formation of a distinct cerebellum were established in the last common ancestor of vertebrates.
Highlights
During development, the cerebellum arises from the dorsal part of rhombomere 1 (r1), just posterior to the midbrain-hindbrain boundary (MHB or isthmic organizer)
Hagfish FGF8/17 was expressed around the MHB, but in a relatively broader domain than that of lamprey and gnathostomes (Supplementary Figure 1C)
Hagfish Ptf1a is expressed at the surface of the fourth ventricle ventral to the Atoh1/Wnt1 expressing region in both lower and upper rhombomeres (Figures 1G,H). These results indicate that the regionalization of the rhombic lip and the ventricular zone are present in hagfish r1 (Figure 1I)
Summary
The cerebellum arises from the dorsal part of rhombomere 1 (r1), just posterior to the midbrain-hindbrain boundary (MHB or isthmic organizer). R1 is defined as an Otxand Hox-negative region and this molecular state is critical for cerebellar development (Broccoli et al, 1999; Katahira et al, 2000; Butts et al, 2014a; Figure 1B). FGF8, a secreted molecular signal from the MHB, plays an important role for the induction of the cerebellum (Reifers et al, 1998; Sato et al, 2001). Wnt, which is expressed in the most caudal part of the midbrain, is known to encode an important signaling molecule. Not directly involved in the induction of the cerebellum, Wnt1-knockout mice lack the cerebellum. This, might be a secondary effect as a result of the disruption of the specification of the midbrain and hindbrain (McMahon and Bradley, 1990)
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