Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools

• DOI: 10.1073/pnas.0904285106
• Publication Date: 2009-10-23T02:06:21Z
• Authors: Milan Joksimovic; Angela Anderegg; Anil Roy; Laura Campochiaro; Beth Yun; Raja Kittappa; Ronald McKay; Rajeshwar Awatramani
• Keywords: Pars compacta

Midbrain dopamine neurons (mDA) are important regulators of diverse physiological functions, including movement, attention, and reward behaviors. Accordingly, aberrant function underlies a wide spectrum disorders, such as Parkinson's disease (PD), dystonia, schizophrenia. The distinct functions the system carried out by neuroanatomically discrete subgroups neurons, which differ in gene expression, axonal projections, susceptibility PD. developmental underpinnings this heterogeneity undefined. We have recently shown that embryonic CNS, mDA originate from midbrain floor plate, ventral midline structure is operationally defined expression molecule Shh. Here, we develop these findings to reveal midbrain, spatiotemporally dynamic Shh domain defines multiple progenitor pools. deduce 3 pools, medial, intermediate, lateral, contribute different clusters. earliest progenitors express Shh, here referred medial pool, contributes rostral linear nucleus tegmental area/interfascicular regions, but remarkably, little substantia nigra pars compacta. intermediate Shh+ give rise all dopaminergic nuclei, SNpc. last lateral pool generates cohort populates red nucleus, Edinger Westphal supraoculomotor cap. Subsequently, produce mDA. This refined ontogenetic definition will expand understanding neuron biology selective susceptibility, impact stem cell-derived therapies models for