Institutionen för cell- och molekylärbiologi (CMB) / Department of Cell and Molecular Biology
Abstract
One of the most challenging questions in developmental biology is how
neurons are specified, acquire their distinct characteristics and find
their correct innervations to form functional circuits. The development
of different subsets of neurons involves the expression of a program
intrinsic to each cell type and the response to extrinsic environmental
influences represented by soluble factors. Breakthroughs in the
understanding of the genetic programs that controls the specification of
ventral cell fates in the spinal cord and hindbrain, have provided useful
tools for the study of similar genetic networks in the more complex
rostral regions of the central nervous system, such as the mesencephalon
(also called midbrain).
Midbrain dopamine (mDA) neurons are born in the ventral midline of the
midbrain and regulate important functions in the brain, including motor
control, cognition, emotions and learning. The degeneration of mDA
neurons is the major hallmark of Parkinson s disease (PD). The lack of
knowledge regarding the factors involving in the early specification of
mDA neurons has been one of the obstacles in applying embryonic stem cell
(ESC)-based replacement therapy for PD. In paper I, we showed that Lmx1a
and Msx1/2 are two key components in the development of mDA neurons.
Lmx1a is necessary and sufficient for the acquisition of the proper mDA
fate by activating the expression of downstream mDA neuron markers, while
Msx1/2 synergizes with Lmx1a by suppressing alternative cell fates and
promoting the progression of neurogenesis. Furthermore, we applied this
knowledge to ESCs and showed that forced expression of Lmx1a could
efficiently induce bona fide mDA neurons. In paper II, we continued to
evaluate the role of Lmx1a in the mouse and compared the function of
Lmx1a with its close homolog Lmx1b during mDA development. Surprisingly,
loss of Lmx1a resulted in a moderate reduction of mDA neurons, which was
partly due to the delayed conversion of floor plate into a neurogenic
region at an early stage. Lmx1b could compensate to large extent for the
loss of Lmx1a in mDA neuron generation as the compound genotype of the
Lmx1 genes displayed a dose-dependent effect. Importantly, we showed that
Lmx1a and Lmx1b have distinct roles in specifying two subgroups, i.e.
medial and lateral mDA neurons. In addition, we revealed the function of
Lmx1b in patterning other ventral cell types, i.e. oculomotor (OM)
neurons and red nucleus (RN) cells. Loss of Lmx1b caused a dramatic
reduction of OM neurons. By contrast, RN cells were born prematurely and
were overproduced. Our current findings establish that Lmx1b influences
the differentiation of multiple neuronal subtypes in the ventral
midbrain, while the activity of Lmx1a in the ventral midbrain appears
devoted to the differentiation of mDA neurons
