Regulatory pathways linking progenitor patterning, cell fates and neurogenesis in the ventral neural tube

Abstract

The assembly of neural circuits in the vertebrate central nervous system depends on the organized generation of specific neuronal subtypes. Studies over recent years have begun to reveal the principles and elucidate some of the detailed mechanisms that underlie these processes. In general, exposure to different types and concentrations of signals directs neural progenitor populations to generate specific subtypes of neurons. These signals function by regulating the expression of intrinsic determinants, notably transcription factors, which specify the fate of cells as they differentiate into neurons. In this review, we illustrate these concepts by focusing on the generation of neurons in ventral regions of the spinal cord, where detailed knowledge of the mechanisms that regulate cell identity has provided insight into the development of a number of neuronal subtypes, including motor neurons. A greater knowledge of the molecular control of neural development is likely to have practical benefits in understanding the causes and consequences of neurological diseases. Moreover, recent studies have demonstrated how an understanding of normal neural development can be applied to direct differentiation of stem cells in vitro to specific neuronal subtypes. This type of rational manipulation of stem cells may represent the first step in the development of treatments based on therapeutic replacement of diseased or damaged nervous tissue.

Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling

“…Among its many functions in mammalian development, the role of Shh in the specification of ventral cell types in the developing neural tube is particularly well understood. For example, spinal motor neurons are induced in response to an intermediate level of Shh, and the number and position of motor neurons within the ventral neural tube is a sensitive indicator of Shh activity (23). We used an HB9-GFP transgenic reporter mouse that expresses GFP in motor neurons (24) (Fig.…”

Sonic Hedgehog Regulates Integrin Activity, Cadherin Contacts, and Cell Polarity to Orchestrate Neural Tube Morphogenesis

“…Mitosis occurs apically and nuclei move toward the basal side where NE cells either reenter the cell cycle or undergo differentiation (Wilcock et al, 2007), allowing the positioning of progenitors that give rise to the spinal cord. Patterning of the neural tube occurs along its dorsoventral axis with motor neurons differentiating ventrally and sensory neurons and neural crest (NC) cells dorsally (Briscoe and Novitch, 2008). Once committed, neural progenitors become located basally while NC cells, unlike other neural cells, disperse through the adjacent tissues.…”

“…Dorsally, BMPs specify sensory cells and NC cells (Liem et al, 1997). Ventrally, Sonic hedgehog (SHH) drives the position and identity of ventral neurons (Briscoe and Novitch, 2008). In addition to BMPs, Wnt proteins also regulate dorsal progenitor proliferation and identity (Muroyama et al, 2002).…”

Temporal and epigenetic regulation of neurodevelopmental plasticity

“…In the spinal cord, homeodomain transcription factors (TCFs) can be classified as either class I or class II depending on their regulation by SHH signalling, where SHH either represses or activates their expression, respectively. A major discovery of Briscoe and colleagues (Briscoe et al 2000;Briscoe & Novitch 2007) was that class I and II genes function as cross-regulatory pairs, and that domains of expression are established by mutual crossrepressive interactions between the class I and the class II factors (figure 3a). The class I and II proteins include members of the NKX, PAX, IRX and DBX families.…”

“…HH, WNT, BMP, FGF) and cell contact (e.g. Notch/delta, integrin)-mediated signalling that confers upon progenitor cells distinct rostrocaudal and dorsoventral positional identities (Briscoe & Novitch 2007) by regulating the expression of specific profiles of transcription factor genes. A key aspect to the patterning process is its temporal regulation.…”