Molecular mechanisms in the formation of the medial longitudinal fascicle

Abstract

The first neurons in the vertebrate brain form a stereotypical array of longitudinal and transversal axon tracts, the early axon scaffold. This scaffold is thought to lay down the basic structure for the later, more complex neuronal pathways in the brain. The ventral longitudinal tract is pioneered by neurons located at the ventral midbrainforebrain boundary, which form the medial longitudinal fascicle. Recent studies have shed some light on the molecular mechanisms that control the development of the medial longitudinal fascicle. Here, we show that patterning molecules, notably the ventralizing signalling molecule Shh, are involved in the formation of medial longitudinal fascicle neurons and in medial longitudinal fascicle axon guidance. Downstream of Shh , several homeobox genes are expressed in the tegmentum. We describe the expression patterns of Sax1 , Emx2 , Six3 , Nkx2.2 and Pax6 in the mesencephalon and pretectum in detail. Furthermore, we review the evidence of their molecular interactions, and their involvement in neuronal fate specification. In particular, Sax1 plays a major role in fate determination of medial longitudinal fascicle neurons. Finally, we discuss the available data on axon guidance mechanisms for the medial longitudinal fascicle, which suggest that different guidance molecules such as class 3 Semaphorins, Slits and Netrins act to determine the caudal and ventral course of the medial longitudinal fascicle axons.

Regulation of downstream neuronal genes by proneural transcription factors during initial neurogenesis in the vertebrate brain

“…Specification of neurons in the neural tube relies on combinations of bHLH and other transcription factors to activate or repress specific neurogenic programs. Homeobox genes, such as, Sax1 could play a role in specifying the nMLF subtypes [46], as gain of function of Sax1 results in an enlargement of the nMLF area [1]. However, other homeobox genes need to be found in order to explain the patterning of the neuronal populations of the early axon scaffold tracts.…”

“…It may be a different mechanism, as these populations of neurons are not distributed along specific axis. Sonic hedgehog (SHH), one of the main signalling molecules involved in neurogenesis patterning [38] is differentially expressed in the ventral forebrain [56] and mostly likely plays a critical role in the formation of the early axon scaffold tracts [1]. …”

Gata2is a tissue-specific post-mitotic selector gene for midbrain GABAergic neurons

“…1B,C,E,F,H,I). Pax6 is also expressed near the Nkx2-2-positive region in the developing midbrain (Ahsan et al, 2007). By combining ISH and IHC, we showed that Pax6 is expressed in a subset of Nkx2-2-positive cells in the ventral m4 domain at E11.5 (see Fig.…”

Early expression of axon guidance molecules in the embryonic chick mesencephalon and pretectum

“…The MLF is formed by neurons located at the ventral MFB that project their axons caudally. The tract runs as a loose bundle adjacent to the floor plate through midbrain and hindbrain towards the spinal cord (Ahsan et al, 2007). The LLF is made up of two groups of neurons: neurons in the mesencephalic nucleus of the trigeminus are found dorsally, close to the roof plate, and send their axons ipsilaterally to the trigeminal ganglion; neurons dispersed in the tectum mostly project contralaterally, growing their axons across the midline before joining the LLF to form the tectobulbar tract.…”

“…The early axon scaffold is made up of several longitudinal, transversal and commissural tracts including the medial longitudinal fascicle (MLF) and the posterior commissure (PC), both originating from the midbrain-forebrain border (MFB) region (reviewed in Ahsan et al, 2007). It has been hypothesised that the early axon scaffold sets up major pathways in the brain by forming substrates for future follower axons Kuwada, 1991, reviewed in Hjorth andKey, 2002).…”