Vincent Y. Wang

Genetic regulation of cerebellar development

The cerebellum is one of the first brain structures to begin to differentiate, yet it is one of the last to achieve maturity — the cellular organization of the cerebellum continues to change for many months after birth. This protracted developmental process creates a special susceptibility to disruptions during embryogenesis and makes the cerebellum highly amenable to study. Over the past few years, genetic research has provided a great deal of information about the molecular events directing the formation of the cerebellum. Knowledge of these mechanisms should enable us to address the nature of human diseases that have their root in developmental processes.

Math1 Expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum

The rhombic lip (RL) is an embryonic proliferative neuroepithelium that generates several groups of hindbrain neurons. However, the precise boundaries and derivatives of the RL have never been genetically identified. We use beta-galactosidase expressed from the Math1 locus in Math1-heterozygous and Math1-null mice to track RL-derived cells and to evaluate their developmental requirements for Math1. We uncover a Math1-dependent rostral rhombic-lip migratory stream (RLS) that generates some neurons of the parabrachial, lateral lemniscal, and deep cerebellar nuclei, in addition to cerebellar granule neurons. A more caudal Math1-dependent cochlear extramural stream (CES) generates the ventral cochlear nucleus and cochlear granule neurons. Similarly, mossy-fiber precerebellar nuclei require Math1, whereas the inferior olive and locus coeruleus do not. We propose that Math1 expression delimits the extent of the rhombic lip and is required for the generation of the hindbrain superficial migratory streams, all of which contribute neurons to the proprioceptive/vestibular/auditory sensory network.

Proprioceptor pathway development is dependent on Math1

The proprioceptive system provides continuous positional information on the limbs and body to the thalamus, cortex, pontine nucleus, and cerebellum. We showed previously that the basic helix-loop-helix transcription factor Math1 is essential for the development of certain components of the proprioceptive pathway, including inner-ear hair cells, cerebellar granule neurons, and the pontine nuclei. Here, we demonstrate that Math1 null embryos lack the D1 interneurons and that these interneurons give rise to a subset of proprioceptor interneurons and the spinocerebellar and cuneocerebellar tracts. We also identify three downstream genes of Math1 (Lh2A, Lh2B, and Barhl1) and establish that Math1 governs the development of multiple components of the proprioceptive pathway.

Atoh1 Null Mice Show Directed Afferent Fiber Growth to Undifferentiated Ear Sensory Epithelia Followed by Incomplete Fiber Retention

Inner ear hair cells have been suggested as attractors for growing afferent fibers, possibly through the release of the neurotrophin brain‐derived neurotrophic factor (BDNF). Atoh1 null mice never fully differentiate hair cells and supporting cells and, therefore, may show aberrations in the growth and/or retention of their innervation. We investigated the distribution of cells positive for Atoh1‐ or Bdnf‐mediated β‐galactosidase expression in Atoh1 null and Atoh1 heterozygotic mice and correlated the distribution of these cells with their innervation. Embryonic day (E) 18.5 Atoh1 null and heterozygotic littermates show Atoh1‐ and BDNF‐β‐galactosidase–positive cells in comparable distributions in the canal cristae and the cochlea apex. Atoh1‐β‐galactosidase–positive but only occasional Bdnf‐β‐galactosidase–positive cells are found in the utricle, saccule, and cochlea base of Atoh1 null mutant mice. Absence of Bdnf‐β‐galactosidase expression in the utricle and saccule of Atoh1 null mice is first noted at E12.5, a time when Atoh1‐β‐galactosidase expression is also first detected in these epithelia. These data suggest that expression of Bdnf is dependent on ATOH1 protein in some but does not require ATOH1 protein in other inner ear cells. Overall, the undifferentiated Atoh1‐ and Bdnf‐β‐galactosidase–positive cells show a distribution reminiscent of that in the six sensory epithelia in control mice, suggesting that ear patterning processes can form discrete patches of Atoh1 and Bdnf expression in the absence of ATOH1 protein. The almost normal growth of afferent and efferent fibers in younger embryos suggests that neither fully differentiated hair cells nor BDNF are necessary for the initial targeted growth of fibers. E18.5 Atoh1 null mice have many afferent fibers to the apex of the cochlea, the anterior and the posterior crista, all areas with numerous Bdnf‐β‐galactosidase–positive cells. Few fibers remain to the saccule, utricle, and the base of the cochlea, all areas with few or no Bdnf‐β‐galactosidase–positive cells. Thus, retention of fibers is possible with BDNF, even in the absence of differentiated hair cells. Developmental Dynamics 233:570–583, 2005.

Drosophila atonal fully rescues the phenotype of Math1 null mice: New functions evolve in new cellular contexts

Many genes share sequence similarity between species, but their properties often change significantly during evolution. For example, the Drosophila genes engrailed and orthodenticle and the onychophoran gene Ultrabithorax only partially substitute for their mouse or Drosophila homologs. We have been analyzing the relationship between atonal (ato) in the fruit fly and its mouse homolog, Math1. In flies, ato acts as a proneural gene that governs the development of chordotonal organs (CHOs), which serve as stretch receptors in the body wall and joints and as auditory organs in the antennae. In the fly CNS, ato is important not for specification but for axonal arborization. Math1, in contrast, is required for the specification of cells in both the CNS and the PNS. Furthermore, Math1 serves a role in the development of secretory lineage cells in the gut, a function that does not parallel any known to be served by ato. We wondered whether ato and Math1 might be more functionally homologous than they appear, so we expressed Math1 in ato mutant flies and ato in Math1 null mice. To our surprise, the two proteins are functionally interchangeable.

Complications of lumboperitoneal shunts

OBJECTIVEPlacement of a lumboperitoneal (LP) shunt is a method for treating communicating hydrocephalus. These shunts can be placed with or without valves. We sought to review the complications associated with the use of LP shunts with the increasing use of horizontal-vertical (HV) valve systems. PATIENTS AND METHODSA retrospective chart review of all patients who received LP shunts at University of California, San Francisco from 1998 to 2005 was performed. RESULTSOf the 74 patients identified in this study, 67 underwent LP shunt placement for the first time, and seven patients had revisions of LP shunts that were originally placed at another hospital. There were a total of 44 revisions for the entire group: 27 patients had one revision, 10 patients had two or three revisions, and one patient had five revisions. Obstruction or migration of the peritoneal catheter was the most common reason for revision. The HV valve was responsible for shunt malfunction in nine patients and was the second-most common site of system problems. Overdrainage symptoms were observed in 11 patients, most of whom had LP shunts without any valve. No patients with an HV valve system developed an acquired Chiari malformation. There were three cases of infection, two of which required removal of the LP shunt. CONCLUSIONOverall, the placement of LP shunts for the treatment of communicating hydrocephalus seems to be a safe procedure. Serious complications such as subdural hematoma were not observed. The HV valve was associated with minor complications, but it was effective in reducing the incidence of overdrainage.

Atoh1-lineal neurons are required for hearing and for the survival of neurons in the spiral ganglion and brainstem accessory auditory nuclei

Atoh1 is a basic helix–loop–helix transcription factor necessary for the specification of inner ear hair cells and central auditory system neurons derived from the rhombic lip. We used the Cre–loxP system and two Cre-driver lines (Egr2Cre and Hoxb1Cre ) to delete Atoh1 from different regions of the cochlear nucleus (CN) and accessory auditory nuclei (AAN). Adult Atoh1-conditional knock-out mice (Atoh1CKO ) are behaviorally deaf, have diminished auditory brainstem evoked responses, and have disrupted CN and AAN morphology and connectivity. In addition, Egr2; Atoh1CKO mice lose spiral ganglion neurons in the cochlea and AAN neurons during the first 3 d of life, revealing a novel critical period in the development of these neurons. These new mouse models of predominantly central deafness illuminate the importance of the CN for support of a subset of peripheral and central auditory neurons.

The use of allograft or autograft and expandable titanium cages for the treatment of vertebral osteomyelitis.

OBJECTIVEThe results of the surgical treatment of osteomyelitis with expandable titanium cages and either allograft or autograft are presented. METHODSThirty-six patients with vertebral osteomyelitis are presented. There were 7 cervical, 17 thoracic, 4 thoracolumbar (involving T12–L1), 5 lumbar, and 3 lumbosacral (involving L5–S1) lesions. The most frequently identified organisms were Staphylococcus aureus, Mycobacterium tuberculosis, and Coccidioides immitis. Imaging studies included x-rays, computed tomographic scans, and magnetic resonance imaging scans. All patients were treated with corpectomies and expandable cage reconstruction. Fusion was performed with rib autograft, iliac crest autograft, or allograft. Most patients who had an anterior approach also underwent posterior instrumentation, whereas a few had anterior instrumentation only. Four patients underwent a posterior approach (transpedicular corpectomy) only. RESULTSThe median follow-up period was 21 months. There were no implant failures. Two recurrences of infection were noted: 1 case involved allograft, and the other involved autograft. At follow-up, neurological deficits improved in all patients, and 81% of patients were pain-free. CONCLUSIONThis study suggests that the treatment of vertebral column osteomyelitis can be performed with expandable titanium cages, and allograft does not appear to increase the rate of recurrence, as compared with autograft.

Vertebral column resection for rigid spinal deformity

OBJECTIVEVertebral column resection (VCR) is a surgical technique that may be applied for correction of moderate to severe spinal deformities, including those with large rigid curves, fixed trunk translation, or asymmetry between the length of the convex and concave column of the deformity. This article reviews the VCR technique as it relates to correction of rigid spinal deformity, including case examples to illustrate its application. METHODSThe literature was reviewed in reference to the use of VCR for correction of rigid spinal deformity. RESULTSVCR involves complete resection of one or more vertebral segments using either combined anterior and posterior approaches or a posterior-only approach and enables significant deformity correction in all three dimensions. Herein, we provide description of the indications, preoperative planning, surgical techniques, complication avoidance, postoperative management, and case examples for VCR. CONCLUSIONVCR enables significant correction of rigid spinal deformities in cases in which less aggressive approaches are not adequate.

PRIMARY DURAL REPAIR DURING MINIMALLY INVASIVE MICRODISCECTOMY USING STANDARD OPERATING ROOM INSTRUMENTS. Commentary

OBJECTIVE Minimally invasive microdiscectomies are commonly being performed for disc herniations. Although inadvertent dural tears are not common, they do occur. Present management of many dural tears includes fibrin glue or other adhesive substances over the dura, tight closure of the fascia and skin, and possibly bedrest. Because these surgeries are usually performed through a small tube, a primary dural repair can be prohibitively difficult. One reason for the difficulty in a primary closure is that the small tube limits the use of proper opening and closing of standard dural repair instruments as well as the proper angulation of the instruments. METHODS To circumvent this difficulty, we have improvised using commonly available instruments in the operating room for primary dural closure. RESULTS We describe our technique and present a video demonstrating the method of primary dural closure without custom-made instruments. CONCLUSION Primary dual repair during minimally invasive microdiscectomy can be performed using standard operation room instruments, including a standard micropituitary ronguer, 5–0 Prolene suture (Ethicon, Inc., Somerville, NJ), and a laparoscopic knot pusher.